KR100326276B1 - Tetrahydrofurane derivatives, producing method thereof and antifungals comprising the same - Google Patents
Tetrahydrofurane derivatives, producing method thereof and antifungals comprising the same Download PDFInfo
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- KR100326276B1 KR100326276B1 KR1019990057618A KR19990057618A KR100326276B1 KR 100326276 B1 KR100326276 B1 KR 100326276B1 KR 1019990057618 A KR1019990057618 A KR 1019990057618A KR 19990057618 A KR19990057618 A KR 19990057618A KR 100326276 B1 KR100326276 B1 KR 100326276B1
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- South Korea
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- methyl
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- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims description 13
- 150000007984 tetrahydrofuranes Chemical class 0.000 title 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000003429 antifungal agent Substances 0.000 claims abstract description 13
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 125000003277 amino group Chemical group 0.000 claims abstract description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 56
- -1 aldehyde compound Chemical class 0.000 claims description 46
- 230000000843 anti-fungal effect Effects 0.000 claims description 22
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 12
- BIIUEEHQYBFXTP-UHFFFAOYSA-N 1-dimethoxyphosphoryl-3-methylbutan-2-one Chemical compound COP(=O)(OC)CC(=O)C(C)C BIIUEEHQYBFXTP-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- RNHVJBJVOGMYMW-UHFFFAOYSA-N 1,3-dimethyl-1-propylurea Chemical compound CCCN(C)C(=O)NC RNHVJBJVOGMYMW-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 12
- 239000000126 substance Substances 0.000 description 43
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 239000013067 intermediate product Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 5
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 5
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 229960004130 itraconazole Drugs 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 4
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 4
- 241000222122 Candida albicans Species 0.000 description 4
- 206010017533 Fungal infection Diseases 0.000 description 4
- 208000031888 Mycoses Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 4
- 229960003942 amphotericin b Drugs 0.000 description 4
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 4
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 4
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 4
- 229960004884 fluconazole Drugs 0.000 description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 3
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 3
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 3
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 3
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- YNCPXBIZAPNQIJ-UHFFFAOYSA-N 1h-imidazole;sodium Chemical compound [Na].C1=CNC=N1 YNCPXBIZAPNQIJ-UHFFFAOYSA-N 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- TZKBVRDEOITLRB-UHFFFAOYSA-N 4-methyl-n-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1h-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2C=C3C=NNC3=NC=2)=C1 TZKBVRDEOITLRB-UHFFFAOYSA-N 0.000 description 3
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- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 3
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- 230000002538 fungal effect Effects 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 삼중 치환된 테트라하이드로푸란 유도체, 이의 제조방법 및 이를 포함하는 항진균제를 제공한다.The present invention provides a trisubstituted tetrahydrofuran derivative represented by the following formula (1) or (2), a preparation method thereof, and an antifungal agent comprising the same.
상기 식에서, X는 CH 또는 질소원자이고, Y는 옥소기 또는 아미노기이고, Z1및 Z2는 서로 독립적으로 F 또는 Cl이다.Wherein X is CH or a nitrogen atom, Y is an oxo group or an amino group, and Z 1 and Z 2 are independently of each other F or Cl.
Description
본 발명은 테트라하이드로푸란 유도체, 이의 제조방법 및 이를 포함하는 항진균제에 관한 것이다.The present invention relates to a tetrahydrofuran derivative, a preparation method thereof and an antifungal agent comprising the same.
진균 감염의 치료는 세균 감염의 치료에 비하여 상당히 어려운 점을 가지고 있다. 그 이유는 진균 감염이 혈관 분포가 적거나 또는 전혀없는 피부, 손톱 및 발톱, 또는 모발 등에 일어나므로 충분한 양의 약물을 분포, 축적시키기가 곤란하기 때문이다.Treatment of fungal infections is quite difficult compared to the treatment of bacterial infections. The reason is that fungal infections occur in skin, nails and toenails, or hairs with little or no blood vessel distribution, and therefore it is difficult to distribute and accumulate a sufficient amount of drugs.
현재 항진균제로 사용되고 있는 약품으로는 다음과 같은 것들이 있다. 스트렙토마이세스 노도수스(Streptomyces nodosus)에서 산출되는 폴리엔 계통의 암포테리신 B와 그 메틸 에스테르가 있다. 이러한 약물은 진균 세포막에 있는 스테롤, 특히 에르고스테롤과 특별한 친화성을 가지고 결합하여, 그 결과 세포막의 투과성을 변화시키고, 세포내용물의 변화를 일으켜 진균의 발육을 억제하거나 사멸시킨다.Drugs that are currently used as antifungal agents include: There is a polyene-based amphotericin B produced by Streptomyces nodosus and its methyl ester. Such drugs bind with sterols, especially ergosterol, in fungal cell membranes with particular affinity, resulting in altered cell membrane permeability and altered cell contents to inhibit or kill fungal growth.
그러나, 상기 암포테리신 B와 그 메틸 에스테르는 주사부위에 정맥염을 일으키거나, 빈혈, 두통, 오한 전율 및 구토 등의 부작용을 가지고 있어 사용시에 상당한 주의를 요한다.However, the amphotericin B and its methyl ester cause phlebitis at the injection site, have side effects such as anemia, headache, tremors and vomiting, and require considerable attention when used.
상기 암포테리신 B와 유사한 폴리엔 계통의 항진균성 물질로는 켄디시딘과 니스타디딘이 있는데, 이들은 상기 암포테리신 B와 유사한 작용기전 및 독성을 보인다.Antifungal substances of the polyene strains similar to the amphotericin B include kendisidin and nistadidine, which show a similar mechanism of action and toxicity to the amphotericin B.
페니실리윰 그리세오풀붐(Penicillium griseofulvum)에서 추출한 항생물질로서 그리세오풀빈은 피부 사상균에 의한 감염질환 치료에 주로 사용되는데, 표피균, 소포자균, 백선균 등의 감염질환에 대해서는 효과를 보이나, 다른 진균에 대해서는 효과가 없다.Antibiotics extracted from Penicillium griseofulvum , Griseofulvin is mainly used to treat infectious diseases caused by skin filamentous fungus. Has no effect on.
다른 항진균 약물로는 불소가 붙은 피리미딘으로서 진균의 사이토신 디아미네이즈에 의해 5-플루오로우라실로 대사되어 RNA 합성을 교란시키는 플루사이토신이 있다. 그러나 이 플루사이토신은 골수기능을 억제하여 빈혈, 백혈구 감소증, 혈소판 감소증 등을 일으키는 부작용을 가지고 있어서 혈액 질환이 있었던 환자 또는 신장기능 장애환자에 대해서는 사용하기가 곤란하다.Another antifungal drug is fluorinated pyrimidine, which is metabolized to 5-fluorouracil by fungal cytosine diamines to disrupt RNA synthesis. However, the flucytosine has side effects of inhibiting bone marrow function and causing anemia, leukopenia, thrombocytopenia, etc., which makes it difficult to use for patients with blood diseases or patients with renal dysfunction.
또 다른 항진균 약물로는 싸이토크롬 P450과 결합하여 에르고스테롤의 생합성에 필요한 라노스테롤 C-14 디메틸레이즈 효소를 억제하는 아졸 계통의 케토코나졸, 이트라코나졸, 플루코나졸, 클로트리마졸, 미코나졸 등과 스쿠알렌 에폭시다제 효소를 차단하는 것으로 알려진 알릴아민 계통의 터비나핀이 있다. 그러나 이들 약물 역시 오심, 구토, 식욕감퇴, 지각이상, 혈소판 감소증 등의 많은 부작용을 나타낸다.Other antifungal drugs include azole-type ketoconazole, itraconazole, fluconazole, clotrimazole, myconazole, and squalene epoxidase enzymes that bind to cytochrome P450 to inhibit the lanosterol C-14 dimethylase enzyme required for the biosynthesis of ergosterol. There is a terbinapine allylamine family known to block. However, these drugs also have many side effects such as nausea, vomiting, loss of appetite, perception and thrombocytopenia.
또한, 최근에는 미국특허 제 3,929,992호 및 미국 특허 제 3,993,749호에서는 마크로라이드계 항생제인 리파마이신의 항진균 활성에 대해 개시하고 있으며, 그 이후에 항진균제로서 다양한 리파마이신 유도체가 제안되었다. 예를 들어, 미국특허 제 4,316,885호, 미국특허 제 4,885,171호, 미국특허 제 4,650,803호 및 미국특허 제 5,151,413호 등을 참조할 수 있다.In addition, US Patent No. 3,929,992 and US Patent No. 3,993,749 have recently disclosed the antifungal activity of lipamycin, a macrolide antibiotic, and various lipamycin derivatives have been proposed as antifungal agents. See, for example, US Pat. No. 4,316,885, US Pat. No. 4,885,171, US Pat. No. 4,650,803, US Pat. No. 5,151,413, and the like.
본 발명자들의 대한민국 특허 공고 제 99-203364호와 문헌(S. K. Chung et al.,Tetrahedron,54, 15899(1998))에서는 새로운 작용기전을 갖는 24-헤테로 원자 치환된 스테로이드 화합물을 개시하고 있으며, 대한민국 특허 제 98-073433호, 미국특허 제 5,039,676호 및 미국특허 제 4,791,111호 등에서는 테트라하이드로푸란 항진균제를 개시하고 있다.Korean Patent Publication No. 99-203364 and the inventors of the present invention (SK Chung et al., Tetrahedron , 54 , 15899 (1998)) disclose a 24-heteroatom-substituted steroid compound having a novel mechanism of action, and a Korean patent Tetrahydrofuran antifungal agents are disclosed in US Pat. No. 98-073433, US Pat. No. 5,039,676, US Pat. No. 4,791,111, and the like.
상술한 바와 같이 다양한 항진균제가 연구 및 사용되고 있지만, 부작용이 감소되고, 전신성 진균 감염증, 특히 아스페르길루스(Aspergillus), 칸디다(Candida) 및 크립토코쿠스(Cryptococcus) 감염증의 치료에 효과적인 활성을 갖는 항진균제의 개발은 현재까지 지속적으로 요구되고 있다.While various antifungal the study and used as described above, side effects are reduced, systemic fungal infections, especially Aspergillus way antifungal agents having a loose (Aspergillus), Candida (Candida) and Cryptococcal kusu (Cryptococcus) effective activity in the treatment of infectious diseases Development continues to be demanded to date.
본 발명이 이루고자 하는 기술적 과제는 신규한 테트라하이드로푸란 유도체를 제공하는 것이다.The technical problem to be achieved by the present invention is to provide a novel tetrahydrofuran derivative.
본 발명이 이루고자 하는 다른 기술적 과제는 상기 테트라하이드로푸란의 제조방법을 제공하는 것이다.Another technical problem to be achieved by the present invention is to provide a method for producing the tetrahydrofuran.
본 발명이 이루고자 하는 또다른 기술적 과제는 상기 테트라하이드로푸란 유도체를 포함하는 항진균제를 제공하기 위한 것이다.Another technical problem to be achieved by the present invention is to provide an antifungal agent comprising the tetrahydrofuran derivative.
상기 기술적 과제를 달성하기 위하여, 본발명은 하기 화학식 1 또는 2로 표시되는 삼중 치환된 테트라하이드로푸란 유도체를 제공한다.In order to achieve the above technical problem, the present invention provides a trisubstituted tetrahydrofuran derivative represented by the following formula (1) or (2).
<화학식 1><Formula 1>
<화학식 2><Formula 2>
상기 식에서, X는 CH 또는 질소원자이고, Y는 옥소기 또는 아미노기이고, Z1및 Z2는 서로 독립적으로 F 또는 Cl이다.Wherein X is CH or a nitrogen atom, Y is an oxo group or an amino group, and Z 1 and Z 2 are independently of each other F or Cl.
본 발명에 있어서, 상기 화학식 1 또는 화학식 2의 Z1및 Z2가 모두 F인 삼중치환된 테트라하이드로푸란 유도체가 바람직하다.In the present invention, trisubstituted tetrahydrofuran derivatives in which Z 1 and Z 2 in Formula 1 or Formula 2 are both F are preferred.
상기 다른 기술적 과제를 달성하기 위하여, 본 발명은,In order to achieve the above another technical problem, the present invention,
(a) 하기 화학식 3으로 표시되는 (2R)-시스 구조 또는 (2R)-트랜스 구조의 알데히드 화합물을 디메틸-3-메틸-2-옥소부틸포스포네이트와 반응시켜 탄소수를 늘이는 단계; 및(a) increasing the carbon number by reacting an aldehyde compound having a (2R) -cis structure or a (2R) -trans structure represented by Formula 3 with dimethyl-3-methyl-2-oxobutylphosphonate; And
(b) 상기 (a)의 반응 결과물을 수소환원시키는 단계를 포함하는 것을 특징으로 하는, 상기 화학식 1 또는 화학식 2에서 X가 N이고 Y가 옥소기인 삼중 치환된 테트라하이드로푸란 유도체의 제조방법을 제공한다.(b) providing a method for preparing a triple substituted tetrahydrofuran derivative wherein X is N and Y is an oxo group in Chemical Formula 1 or Chemical Formula 2, comprising the step of hydrogen reduction of the reaction product of (a). do.
상기 식에서, Z1및 Z2는 서로 독립적으로 F 또는 Cl이다.Wherein Z 1 and Z 2 are independently of each other F or Cl.
상기 다른 기술적 과제를 달성하기 위한 다른 실시예에 의한 본 발명은,The present invention according to another embodiment for achieving the other technical problem,
(a) 하기 화학식 4로 표시되는 (2R)-시스 구조 또는 (2R)-트랜스 구조의 알데히드 화합물을 디메틸-3-메틸-2-옥소부틸포스포네이트와 반응시켜 탄소수를 늘이는 단계;(a) increasing the carbon number by reacting an aldehyde compound having a (2R) -cis structure or a (2R) -trans structure represented by Formula 4 with dimethyl-3-methyl-2-oxobutylphosphonate;
(b) 상기 (a) 단계의 생성물을 수소환원시켜 하기 화학식 5로 표시되는 화합물의 (2R)-시스 구조 또는 (2R)-트랜스 구조의 화합물을 제조하는 단계; 및(b) hydrogen-reducing the product of step (a) to prepare a compound of (2R) -cis structure or (2R) -trans structure of the compound represented by the following formula (5); And
(c) 하기 화학식 5로 표시되는 화합물을 토실레이션시키고, 친핵 치환반응시키는 단계를 포함하는 것을 특징으로 하는, 상기 화학식 1 또는 화학식 2에서 X가 CH이고 Y가 옥소기인 삼중 치환된 테트라하이드로푸란 유도체의 제조방법을 제공한다.(c) triple-substituted tetrahydrofuran derivative wherein X is CH and Y is oxo group in the above formula (1) or (2), comprising the step of tosylation and nucleophilic substitution of the compound represented by the following formula (5): It provides a method of manufacturing.
상기 식들에서, Z1및 Z2는 서로 독립적으로 F 또는 Cl이다.In the above formulas, Z 1 and Z 2 are independently of each other F or Cl.
상기 제조방법 중 단계 (c)의 친핵 치화반응이 N,N'-디메틸프로필우레아 용매에서 실시되는 것이 바람직하다.It is preferred that the nucleophilic reaction of step (c) in the above production process is carried out in a N, N'-dimethylpropylurea solvent.
상기 다른 기술적 과제를 달성하기 위한 다른 실시예에 의한 본 발명은,The present invention according to another embodiment for achieving the other technical problem,
(a) 상술한 제조방법들에 의해 제조된 Y가 옥소기인 화합물을 하이드록실아민과 반응시켜 옥심화합물을 제조하는 단계; 및(a) preparing an oxime compound by reacting a compound in which Y is an oxo group prepared by the above-described preparation methods with hydroxylamine; And
(b) 상기 옥심 화합물을 아민으로 환원시키는 단계를 포함하는 것을 특징으로 하는, 상기 화학식 1 또는 화학식 2에서 X가 N 또는 CH이고, Y가 아미노기인 화합물을 제조하는 방법을 제공한다.(b) reducing the oxime compound to an amine, wherein X is N or CH, and Y is an amino group.
본 발명의 실시예에 따르면, 상기 제조방법들에 사용되는 상기 화학식 3 또는 화학식 4로 표시되는 화합물은According to an embodiment of the present invention, the compound represented by the formula (3) or formula (4) used in the production methods
(a) 하기 화학식 6 또는 화학식 7로 표시되는 (2R)-시스 구조 또는 (2R)-트랜스 구조의 토실레이트 화합물을 시아나이드 금속염과 반응시켜 하기 화학식 8 또는 9로 표시되는 화합물의 (2R)-시스 구조 또는 (2R)-트랜스 구조의 시아나이드 화합물을 제조하는 단계; 및(a) (2R)-of the compound represented by the following formula (8) or (9) by reacting a tosylate compound having a (2R) -cis structure or (2R) -trans structure represented by the following formula (6) or (7) with a cyanide metal salt Preparing a cyanide compound of cis structure or (2R) -trans structure; And
(b) 상기 (a) 단계의 생성물을 알데하이드로 환원시키는 단계를 포함하는 제조방법에 의해 제조될 수 있다.(b) may be prepared by a manufacturing method comprising the step of reducing the product of step (a) to aldehyde.
상기 식들에서, Z1및 Z2는 서로 독립적으로 F 또는 Cl이고, OTs는 토실레이트이다.In the above formulas, Z 1 and Z 2 are independently of each other F or Cl, and OTs are tosylate.
상기 또 다른 기술적 과제를 달성하기 위하여, 본 발명은 약학적으로 허용가능한 담체와 함께 상기 화학식 1 또는 화학식 2의 화합물을 항진균적으로 유효량포함하는 것을 특징으로 하는 항진균제를 제공한다.In order to achieve the above another technical problem, the present invention provides an antifungal agent comprising an antifungal effective amount of the compound of Formula 1 or Formula 2 together with a pharmaceutically acceptable carrier.
본 발명에 있어서, 상기 약학적 조성물은 경구 또는 비경구 투여용일 수 있다.In the present invention, the pharmaceutical composition may be for oral or parenteral administration.
본 발명자들은 항진균 활성을 갖는 24-헤테로 원자 치환된 스테로이드 화합물을 모사한 테트라하이드로푸란 유도체의 제조 및 항진균 활성에 대해 연구하던 중 상기 화학식 1 또는 2로 표시되는 테트라하이드로푸란 유도체가 우수한 항진균 활성을 갖고 있음을 알게되어 본 발명을 완성을 완성하게 된 것이다.The inventors of the present invention studied the preparation and antifungal activity of tetrahydrofuran derivatives simulating a 24-hetero atom substituted steroid compound having antifungal activity, and the tetrahydrofuran derivative represented by Formula 1 or 2 has excellent antifungal activity. It was found that complete the present invention.
또한, 본 발명에 따른 테트라하이드로푸란 유도체 중에 상기 화학식 1 또는 화학식 2의 Z1및 Z2가 모두 F인 경우, 즉 하기 화학식 10 내지 17로 표시되는 화합물의 경우에 더욱 우수한 항진균 활성을 보인다는 것도 발견하게 되었다.In addition, it seems tetrahydrofuran, if the formula (1) or the Z 1 and Z 2 of formula (2) is all F in the derivative, that is to more excellent antifungal activity in the case of the compound represented by the general formula 10 to 17 according to the invention Found out.
이하, 본 발명에 따른 삼중 치환된 테트라하이드로푸란 유도체의 제조방법의 설명을 통하여 본 발명을 상세히 설명하고자 한다.Hereinafter, the present invention will be described in detail through a description of a method for preparing a triple substituted tetrahydrofuran derivative according to the present invention.
상기 화학식 1 또는 화학식 2로 표시되는 화합물들은 하기 반응식 1 및 2로 나타낸 방법으로 제조할 수 있다.Compounds represented by Formula 1 or Formula 2 may be prepared by the methods shown in Schemes 1 and 2.
하기 반응식 1은 상기 화학식 1 또는 2에 있어서, Y와 Z는 상술한 바와 같고 X가 질소원자인 경우의 화합물을 제조하기 위한 반응식이며, 하기 반응식 2는 X가 CH인 경우의 화합물을 제조하기 위한 반응식이다.Reaction Scheme 1 is a chemical formula for preparing a compound when Y and Z are the same as described above and X is a nitrogen atom in Formula 1 or 2, and Scheme 2 is a reaction formula for preparing a compound when X is CH. to be.
상기 반응식 1 및 반응식 2에 있어서,a는 (2R)-시스 구조의 화합물을 나타내고,b는 (2R)-트랜스 구조의 화합물을 나타낸다. 또한, Z1및 Z2는 서로 독립적으로 F 또는 Cl이다.In Scheme 1 and Scheme 2, a represents a compound having a (2R) -cis structure, and b represents a compound having a (2R) -trans structure. In addition, Z 1 and Z 2 are independently of each other F or Cl.
상기 반응식 1에 나타낸 제조방법을 구체적으로 살펴보면 다음과 같다.Looking at the production method shown in Scheme 1 in detail.
먼저, 반응식 1의1a및1b의 토실레이트 화합물은 대한민국 특허 공개 공보 1998-073433 및 문헌(A.K. Saksena et. al., Bioorg, Med. Chem, Lett. 4(16), 2023(1994))에 개시된 방법에 따라 제조할 수 있다.First, the tosylate compounds of Scheme 1 1a and 1b are disclosed in Korean Patent Laid-Open Publication No. 1998-073433 and in AK Saksena et. Al., Bioorg, Med. Chem, Lett. 4 (16), 2023 (1994). It can manufacture according to a method.
다음으로, 상기 화합물1a및1b를 KCN 또는 NaCN과 같은 시아나이드 금속염과 반응시켜3a및3b의 시아나이드 화합물을 제조하고, 이어서 상기 시아나이드 화합물을 환원시켜5a및5b의 알데하이드 화합물을 제조한다. 이 때 알데하이드로의 환원반응에 사용할 수 있는 화합물의 예로는 디이소부틸알루미늄하이드라이드를 들 수 있다.Next, the compounds 1a and 1b are reacted with a cyanide metal salt such as KCN or NaCN to prepare cyanide compounds of 3a and 3b , and then the cyanide compounds are reduced to prepare aldehyde compounds of 5a and 5b . At this time, examples of the compound which can be used for the reduction reaction to aldehyde include diisobutyl aluminum hydride.
계속해서, 알데하드 화합물5a및5b를 디메틸-3-메틸-2-옥소부틸포스포네이트와 반응시키고, 이어서 수소환원 반응을 시켜 케톤화합물7a및7b를 제조한다. 이 때 수소환원 반응의 촉매로는 팔라듐/활성탄 촉매를 사용할 수 있다.Subsequently, the aldehyde compounds 5a and 5b are reacted with dimethyl-3-methyl-2-oxobutylphosphonate, followed by a hydrogen reduction reaction to prepare ketone compounds 7a and 7b . At this time, palladium / activated carbon catalyst may be used as a catalyst for the hydrogen reduction reaction.
상술한 바와 같이 제조된 케톤화합물7a및7b를 하이드록실아민과 반응시켜 옥심화합물을 얻고, 이 옥심화합물을 니켈(II)클로라이드육수화물과 소디움보로하이드라이드를 사용하여 옥심을 아민으로 환원시켜 화합물9a및9b를 제조한다.The ketone compounds 7a and 7b prepared as described above are reacted with hydroxylamine to obtain an oxime compound, and the oxime compound is reduced to amine using nickel (II) chloride hexahydrate and sodium borohydride. 9a and 9b are prepared.
다음으로, 상기 반응식 2에 나타낸 제조방법을 구체적으로 살펴보면 다음과 같다.Next, look at in detail the manufacturing method shown in Scheme 2.
먼저, 반응식 2의2a및2b의 토실레이트 화합물은 상기 반응식 1의1a및1b의 화합물을 제조하는 방법에서 트리아졸 대신에 벤질알콜을 사용하여 제조할 수있으며, 이 때 (2R)-시스 화합물과 (2R)-트랜스 화합물의 혼합물 상태로 얻어지나, 분별결정과 관 크로마토그래피를 사용하여2a와2b를 분리할 수 있으며, NMR 스펙트럼으로 확인한 결과 각 이성질체의 순도가 95%de 이상임을 확인할 수 있다.First, the tosylate compounds of 2a and 2b of Scheme 2 may be prepared using benzyl alcohol instead of triazole in the process for preparing compounds of 1a and 1b of Scheme 1, wherein (2R) -cis compound and Obtained in the form of a mixture of (2R) -trans compounds, 2a and 2b can be separated by fractional crystallization and column chromatography, and confirmed by NMR spectrum, the purity of each isomer is 95% de or more.
토실레이트 화합물2a및2b를 이용하여 시아나이드 화합물4a및4b, 알데하이드 화합물6a및6b, 하이드록시 케톤 화합물 8a 및 8b를 제조하는 방법은 상기 반응식 1에 대한 설명에서와 동일한 방법으로 제조할 수 있다.The cyanide compounds 4a and 4b , the aldehyde compounds 6a and 6b , and the hydroxy ketone compounds 8a and 8b using tosylate compounds 2a and 2b may be prepared by the same method as described for Scheme 1 above.
상기 하이드록시 케톤화합물8a및8b를 p-톨루엔설포닐클로라이드와 반응시켜 토실레이트 화합물10a및10b를 얻을 수 있다. 이 토실레이트 화합물10a및10b를 N, N'-디메틸프로필렌우레아 용매에서 소디움이미다졸과 반응시켜 이미다졸 케톤화합물11a및11b를 제조한다.The hydroxy ketone compounds 8a and 8b may be reacted with p-toluenesulfonyl chloride to obtain tosylate compounds 10a and 10b . The tosylate compounds 10a and 10b are reacted with sodium imidazole in a N, N'-dimethylpropyleneurea solvent to prepare imidazole ketone compounds 11a and 11b .
화합물10a및10b의 토실레이트는 네오펜틸 구조를 가지고 있어서, 일반적으로 친핵 치환반응이 매우 어려운 것으로 알려져 있으나, N, N'-디메틸프로필렌우레아 용매를 사용하면 효과적으로 친핵 친환반응을 수행할 수 있다.The tosylate of the compounds 10a and 10b has a neopentyl structure, and generally, nucleophilic substitution reactions are known to be very difficult. However, when N, N'-dimethylpropylene urea solvents are used, nucleophilic reactions can be effectively performed.
다음으로, 상기 이미다졸 케톤화합물11a및11b를 하이드록실아민과 반응시켜 옥심화합물을 얻고, 이 옥심화합물을 니켈(II)클로라이드육수화물과 소디움보로하이드라이드를 사용하여 옥심을 아민으로 환원시켜 화합물12a및12b를 제조한다.Next, the imidazole ketone compounds 11a and 11b are reacted with hydroxylamine to obtain an oxime compound, and the oxime compound is reduced to amine by using nickel (II) chloride hexahydrate and sodium borohydride. 12a and 12b are prepared.
또한, 상기 반응식 1과 2에서는 나타내지 않았지만, 토실레이트 화합물10a및10b를 소디움트리아졸과 반응시켜 화합물7a및7b를 제조할 수도 있다.In addition, although not shown in Schemes 1 and 2, compounds 7a and 7b may be prepared by reacting tosylate compounds 10a and 10b with sodium triazole.
상술한 바와 같이 제조된 삼중 치환된 테트라하이드로푸란 유도체를 활성성분으로서 약학적으로 허용가능한 담체와 함께 또는 단독으로 진균 감염 질환을 치료하기 위해 포유동물에 투여될 수 있다. 상기 약학적으로 허용가능한 담체는 고체 또는 액체일 수 있다.Triple-substituted tetrahydrofuran derivatives prepared as described above can be administered to a mammal for the treatment of fungal infection diseases, either alone or in combination with a pharmaceutically acceptable carrier as an active ingredient. The pharmaceutically acceptable carrier may be solid or liquid.
고체 담체는 방향제, 활택제, 현탁화제, 충진제, 결합제, 코팅제 또는 붕해제로서도 작용할 수 있는 하나 이상의 물질을 포함한다. 또한 상기 담체는 캡슐화제일 수 도 있다. 약학적 조성물이 산제인 경우에는 상기 담체는 미세 분말화된 활성성분과 혼합되는 미세 분말 고체이며, 정제일 경우에는 활성 성분은 적절한 비율에서 원하는 크기와 모양으로 성형가능한 담체와 혼합된다.Solid carriers include one or more materials that can also act as fragrances, lubricants, suspending agents, fillers, binders, coatings, or disintegrants. The carrier may also be an encapsulant. When the pharmaceutical composition is a powder, the carrier is a fine powder solid which is mixed with the finely powdered active ingredient, and in tablets the active ingredient is mixed with a carrier which is moldable to the desired size and shape at an appropriate ratio.
상술한 바와 같은 고체 담체의 적절한 예로는 칼슘 포스페이트, 마그네슘 스테아레이트, 탈크, 설탕, 젖당, 덱스트린, 셀룰로오스, 메틸 셀룰로오스, 소디움 카르복시메틸 셀룰로오스, 폴리비닐피롤리딘, 이온 교환 수지등을 들 수 있다.Suitable examples of solid carriers as described above include calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, ion exchange resins and the like.
액체 담체는 액제, 현탁제, 유제, 엘릭실제, 시럽제, 연고제 등을 제조하기 위하여 사용될 수 있다. 활성성분은 약학적 허용가능한 물, 유기 용매, 오일 또는 지방, 또는 이들의 혼합물에 용해되거나 분산될 수 있다. 상기 액체 담체는 유화제, 완충제, 보존제, 방향제, 현탁제, 점증제, 안정화제, 삼투압 조절제 등의 다른 적절한 약학적으로 허용가능한 부형제를 포함할 수 있다.Liquid carriers can be used to prepare solutions, suspensions, emulsions, elixirs, syrups, ointments and the like. The active ingredient may be dissolved or dispersed in pharmaceutically acceptable water, organic solvents, oils or fats, or mixtures thereof. The liquid carrier may comprise other suitable pharmaceutically acceptable excipients such as emulsifiers, buffers, preservatives, fragrances, suspending agents, thickeners, stabilizers, osmotic pressure regulators and the like.
경구 또는 비경구 투여를 위한 액체 담체의 적절한 예로는 물 또는 소디움 카르복시메틸 셀루로오스와 같은 셀룰로오스 유도체와 같은 부형제를 소정량 포함하는 물, 모노하이드릭 알콜, 폴리하이드릭 알콜 등을 포함하는 알콜류 또는 이들의 유도체 및 에틸 올레이트와 같은 오일 에스테르 등을 들 수 있다. 또한 에어로솔제를 위한 액체 담체로는 할로겐화 하이드로카본 또는 다른 약학적으로 허용가능한 분사제가 있다.Suitable examples of liquid carriers for oral or parenteral administration include alcohols including water, monohydric alcohols, polyhydric alcohols, etc., containing a predetermined amount of excipients such as water or cellulose derivatives such as sodium carboxymethyl cellulose, or Derivatives thereof and oil esters such as ethyl oleate. Liquid carriers for aerosols also include halogenated hydrocarbons or other pharmaceutically acceptable propellants.
멸균된 액제 또는 현탁액제와 같은 액상 약학적 조성물은 근육주사, 피하주사, 복강주사 등에 의해 투여될 수 있으며, 또한, 멸균된 액제는 정맥주사도 가능하다.Liquid pharmaceutical compositions such as sterile liquids or suspensions may be administered by intramuscular injection, subcutaneous injection, intraperitoneal injection, or the like, and the sterile liquid formulations may also be intravenously injected.
이하, 실시예를 통하여 본 발명은 더욱 상세히 설명하고자 한다. 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. The scope of the present invention is not limited to the following examples.
<실시예 1><Example 1>
(-)-(2R-시스)2-(2,4-디플루오로페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-4-(5-메틸-4-옥소헥실)테트라하이드로푸란의 제조(-)-(2R-cis) 2- (2,4-difluorophenyl) -2- [1H- (1,2,4-triazol-1-yl) methyl] -4- (5-methyl Preparation of -4-oxohexyl) tetrahydrofuran
본 실시예에서 제조하고자 하는 화합물은 상기 화학식 10으로 표시되는 화합물로서 반응식 1에서7a화합물 중 Z1및 Z2가 모두 F인 화합물(이하7a'로 표시)이다.The compound to be prepared in the present Example is a compound represented by Chemical Formula 10, wherein Z 1 and Z 2 in the 7a compound of Scheme 1 are both F (hereinafter referred to as 7a ′ ).
단계 1:Step 1:
화학적 특징이 다음과 같은 (-)-(2R-시스)-2-(2,4-디플루오닐페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-테트라하이드로-4-푸란메탄올,4-톨루엔설포네이트(반응식 1의 화합물1a중 Z1및 Z2가 모두 F인 경우)(이하1a'로 표시) 930mg과 KCN 202mg을 디메틸설폭사이드 10ml에 녹이고, 55℃에서 하루 밤 동안 교반하였다. 이 용액에 에틸아세테이트 50ml을 가하여 희석시키고, 유기층을 정제수로 세척한 후무수 마그네슘설페이트로 건조시키고 불용성 물질을 여과하였다. 이어서, 여액을 감압농축하여 얻어진 잔사를 에틸아세테이트-헥산에서 결정화시켜 (-)-(2R-시스)-2-(2,4-디플루오닐페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-4-(시아노메틸)테트라하이드로푸란(반응식1의 화합물3a중 Z1및 Z2가 모두 F인 경우)(이하3a'로 표시) 533mg을 제조하였다.(-)-(2R-cis) -2- (2,4-difluorylphenyl) -2- [1H- (1,2,4-triazol-1-yl) methyl] Tetrahydro-4-furanmethanol, 4-toluenesulfonate (when Z 1 and Z 2 in compound 1a of Scheme 1 are both F) (hereinafter referred to as 1a ' ) and 930 mg and 202 mg of KCN are dissolved in 10 ml of dimethyl sulfoxide. Stir at 55 ° C. overnight. 50 ml of ethyl acetate was added to this solution, the organic layer was washed with purified water, dried over anhydrous magnesium sulfate, and the insoluble substance was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was then crystallized in ethyl acetate-hexane to give (-)-(2R-cis) -2- (2,4-difluoroylphenyl) -2- [1H- (1,2, Prepare 533 mg of 4-triazol-1-yl) methyl] -4- (cyanomethyl) tetrahydrofuran (when Z 1 and Z 2 in compound 3a of Scheme 1 are both F) (hereinafter referred to as 3a ' ) It was.
화합물1a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 1a ' :
녹는점 97-99℃:[α]D-41.57(c 0.9, CHCl3);1H-NMR(CDCl3)δ 1.90(m, 1H), 2.46(m, 5H), 3.57(dd, J=9.1, 6.2Hz, 1H), 3.69(dd, J=9.8, 7.5Hz, 1H), 3.84(dd, J=9.8, 5.6Hz, 1H), 3.98(dd, J=8.9, 7.2Hz, 1H), 4.46(d, J=14.4Hz, 1H), 4.54(d, J=14.3Hz, 1H), 6.82(m, 2H), 7.33(m, 3H), 7.75(m, 3H), 8.03(s, 1H); IR(CHCl3)ν 1616, 1501, 1361, 1272, 1176cm-1.Melting point 97-99 ° C.:[α] D −41.57 (c 0.9, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.90 (m, 1H), 2.46 (m, 5H), 3.57 (dd, J = 9.1, 6.2 Hz, 1H), 3.69 (dd, J = 9.8, 7.5 Hz, 1H) , 3.84 (dd, J = 9.8, 5.6 Hz, 1H), 3.98 (dd, J = 8.9, 7.2 Hz, 1H), 4.46 (d, J = 14.4 Hz, 1H), 4.54 (d, J = 14.3 Hz, 1H), 6.82 (m, 2H), 7.33 (m, 3H), 7.75 (m, 3H), 8.03 (s, 1H); IR (CHCl 3 ) ν 1616, 1501, 1361, 1272, 1176 cm −1 .
화합물3a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 3a ' :
녹는점 113.5-114.4℃:[α]D-57.33(c 0.5, CHCl3);1H-NMR(CDCl3)δ 2.08(dd, J=13.0, 8.6Hz, 1H), 2.20(d, J=6.9Hz, 2H), 2.63(m, 1H), 3.56(dd, J=8.9, 7.2Hz, 1H), 4.11(dd, J=8.8, 7.1Hz, 1H), 4.49(d, J=14.4Hz, 1H), 4.64(d, J=14.4Hz, 1H), 6.85(m, 2H), 7.36(m, 1H), 7.83(s, 1H), 8.10(s, 1H); IR(CHCl3)ν 2246, 1615cm-1.Melting point 113.5-114.4 ° C .: [α] D −57.33 (c 0.5, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 2.08 (dd, J = 13.0, 8.6 Hz, 1H), 2.20 (d, J = 6.9 Hz, 2H), 2.63 (m, 1H), 3.56 (dd, J = 8.9, 7.2 Hz, 1H), 4.11 (dd, J = 8.8, 7.1 Hz, 1H), 4.49 (d, J = 14.4 Hz, 1H), 4.64 (d, J = 14.4 Hz, 1H), 6.85 (m, 2H) , 7.36 (m, 1 H), 7.83 (s, 1 H), 8.10 (s, 1 H); IR (CHCl 3 ) ν 2246, 1615 cm −1 .
단계 2:Step 2:
상기 단계 1에서 제조한 화합물3a'488mg을 톨루엔 8ml에 용해시키고, -65℃로 냉각시킨 후 1M 농도의 디이소부틸알루미늄하이드라이드/톨루엔 용액 2ml를 부가하였다. 서서히 반응온도가 상승하여 상온이 될 때까지 상기 용액을 방치한 후 4시간 동안 교반한 후 포화 암모늄클로라이드 수용액으로 반응을 종결시켰다. 이 반응물을 에틸아세테이트에 희석시키고, 포화 소금수로 세척하였다. 다음으로, 무수 마그네슘설페이트로 건조시키고 불용성 물질을 여과하였다. 이어서, 여액을 감압농축하여 얻어진 잔사를 관 크로마토그래프로 분리하여 (-)-(2R-시스)-2-(2,4-디플루오닐페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-4-(포밀메틸)테트라하이드로푸란(반응식1의 화합물 5a 중 Z1및 Z2가 모두 F인 경우)(이하 5a'로 표시) 256mg을 제조하였다.488 mg of the compound 3a ' prepared in Step 1 was dissolved in 8 ml of toluene, cooled to −65 ° C., and 2 ml of diisobutylaluminum hydride / toluene solution at a concentration of 1 M was added. After slowly increasing the reaction temperature to room temperature, the solution was left to stir for 4 hours, and then the reaction was terminated with a saturated aqueous ammonium chloride solution. The reaction was diluted with ethyl acetate and washed with saturated brine. Next, it was dried over anhydrous magnesium sulfate and the insoluble material was filtered out. The residue obtained by concentrating the filtrate under reduced pressure was then separated by column chromatography to obtain (-)-(2R-cis) -2- (2,4-difluoroylphenyl) -2- [1H- (1,2,4). 256 mg of -triazol-1-yl) methyl] -4- (formylmethyl) tetrahydrofuran (when Z 1 and Z 2 in compound 5a of Scheme 1 are both F) (denoted as 5a 'below) was prepared.
화합물5a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 5a ' :
녹는점 62.4-63.6℃:[α]D-56.4(c 0.5, CHCl3);1H-NMR(CDCl3)δ 2.47(m, 4H), 2.47(m, 1H), 4.47(d, J=14.3Hz, 1H), 4.63(d, J=14.3Hz, 1H), 6.84(m, 2H), 7.36(m, 1H), 7.84(s, 1H), 8.12(s, 1H), 9.67(s, 1H); IR(CHCl3)ν 2729, 1722 cm-1.Melting point 62.4-63.6 ° C.:[α] D −56.4 (c 0.5, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 2.47 (m, 4H), 2.47 (m, 1H), 4.47 (d, J = 14.3 Hz, 1H), 4.63 (d, J = 14.3 Hz, 1H), 6.84 (m , 2H), 7.36 (m, 1H), 7.84 (s, 1H), 8.12 (s, 1H), 9.67 (s, 1H); IR (CHCl 3 ) ν 2729, 1722 cm −1 .
단계 3:Step 3:
디메틸-3-메틸-2-옥소부틸포스포네이트 153mg, 1,8-디아자바이싸이클로[5,4,0]-7-운데센 120mg과 리튬클로라이드 33.4mg을 아세토니트릴 1ml에 용해시켰다. 별도로 단계 2에서 제조한 화합물5a'220mg을 아세토니트릴 6ml에 녹여 제조한 용액을 상기 용액에 부가하고 상온에서 1시간 동안 교반하였다. 이러한 반응액을 에틸아세테이트에 희석하고, 5% NaH2PO4와 소금수로 세척한 다음 무수 마그네슘설페이트로 건조시키고 불용성 물질을 여과하였다. 이어서, 여액을 농축하여 얻어진 잔사 244mg 중 210mg을 무수에탄올 10ml에 녹이고, 5% 활성탄/팔라듐 촉매 30mg를 넣고 수소환원 반응을 시켰다. 이 반응물에서 불용물을 여과하고, 여액을 농축하여 얻은 잔사를 관 크로마토그래프로 분리하여 목적물인 상기 화학식 10의 화합물7a'171mg을 제조하였다.153 mg of dimethyl-3-methyl-2-oxobutylphosphonate, 120 mg of 1,8-diazabicyclo [5,4,0] -7-undecene and 33.4 mg of lithium chloride were dissolved in 1 ml of acetonitrile. Separately, a solution prepared by dissolving 220 mg of Compound 5a ' prepared in Step 2 in 6 ml of acetonitrile was added to the solution and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with 5% NaH 2 PO 4 and brine, dried over anhydrous magnesium sulfate, and the insoluble substance was filtered out. Subsequently, 210 mg of the residue obtained by concentrating the filtrate was dissolved in 10 ml of anhydrous ethanol, and 30 mg of 5% activated carbon / palladium catalyst was added to undergo a hydrogen reduction reaction. Insoluble matters were filtered out from the reaction mixture, and the residue obtained by concentrating the filtrate was separated by column chromatography to prepare 171 mg of a compound 7a ' .
화합물 7a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 7a ':
[α]D-32.38(c 0.5, CHCl3);1H-NMR(CDCl3)δ 1.05(s, 3H), 1.07(s, 3H), 1.21(m, 2H), 1.45(m, 2H), 1.70(dd, J=12.5, 10.6Hz, 1H), 2.05(m, 1H), 2.38(t, 2H), 2.47(m, 1H), 2.54(m, 1H), 3.37(t, 1H), 4.10(t, 1H), 4.51(d, J=14.3Hz, 1H), 4.60(d, J=14.3Hz, 1H), 6.82(m, 2H), 7.36(m, 1H), 7.80(s, 1H), 8.11(s, 1H); IR(CHCl3)ν 1708cm-1.[α] D -32.38 (c 0.5, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.05 (s, 3H), 1.07 (s, 3H), 1.21 (m, 2H), 1.45 (m, 2H), 1.70 (dd, J = 12.5, 10.6 Hz, 1H) , 2.05 (m, 1H), 2.38 (t, 2H), 2.47 (m, 1H), 2.54 (m, 1H), 3.37 (t, 1H), 4.10 (t, 1H), 4.51 (d, J = 14.3 Hz, 1H), 4.60 (d, J = 14.3 Hz, 1H), 6.82 (m, 2H), 7.36 (m, 1H), 7.80 (s, 1H), 8.11 (s, 1H); IR (CHCl 3 ) ν 1708 cm −1 .
<실시예 2><Example 2>
(-)-(2R-트랜스)2-(2,4-디플루오로페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-4-(5-메틸-4-옥소헥실)테트라하이드로푸란의 제조(-)-(2R-trans) 2- (2,4-difluorophenyl) -2- [1H- (1,2,4-triazol-1-yl) methyl] -4- (5-methyl Preparation of -4-oxohexyl) tetrahydrofuran
본 실시예에서 제조하고자 하는 화합물은 상기 화학식 11로 표시되는 화합물로서 반응식 1에서7b화합물 중 Z1및 Z2가 모두 F인 화합물(이하7b'로 표시)이다.The compound to be prepared in the present Example is a compound represented by Chemical Formula 11, wherein Z 1 and Z 2 in the 7b compound of Scheme 1 are both F (hereinafter referred to as 7b ′ ).
단계 1:Step 1:
화학적 특징이 다음과 같은 (-)-(2R-트랜스)-2-(2,4-디플루오닐페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-테트라하이드로-4-푸란메탄올,4-톨루엔설포네이트(반응식 1의 화합물1b중 Z가 F인 경우)(이하1b'로 표시) 1.69g, KCN 367mg을 디메틸설폭사이드 20ml을 사용한 것을 제외하고는 실시예 1의 단계 1에서와 동일한 방법을 사용하고, 관 크로마토그래프로 분리하여 (-)-(2R-트랜스)-2-(2,4-디플루오닐페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-4-(시아노메틸)테트라하이드로푸란(반응식1의 화합물3b중 Z1및 Z2가 모두 F인 경우)(이하3b'로 표시) 1.12g을 제조하였다.(-)-(2R-trans) -2- (2,4-difluorylphenyl) -2- [1H- (1,2,4-triazol-1-yl) methyl] Tetrahydro-4-furanmethanol, 4-toluenesulfonate (when Z in compound 1b of Scheme 1 is F) (hereinafter denoted as 1b ' ), except that 169 g of KCN 367 mg, 20 ml of dimethyl sulfoxide was used. Using the same method as in step 1 of Example 1, the reaction mixture was separated by column chromatography to give (-)-(2R-trans) -2- (2,4-difluoroylphenyl) -2- [1H- (1 , 2,4-triazol-1-yl) methyl] -4- (cyanomethyl) tetrahydrofuran (when Z 1 and Z 2 in compound 3b of Scheme 1 are both F) (hereinafter referred to as 3b ' ) 1.12 g was prepared.
화합물1b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 1b ' :
[α]D-19.77(c 1, CHCl3);1H-NMR(CDCl3)δ 1.91(ddd, J=13.6, 7.5, 2.0Hz, 1H), 2.14(m, 1H), 2.63(ddd, J=13.5, 8.4, 2.3Hz, 1H), 3.56(dd, J=8.8, 7.7Hz, 1H), 3.74(m, 2H), 3.98(dd, J=8.9, 6.8Hz, 1H), 4.31(d, J=14.3Hz, 1H), 4.50(d, J=14.2Hz, 1H), 6.80(m, 2H), 7.34(m, 3H), 7.65(s, 1H), 7.67(s, 1H), 7.81(s, 1H), 8.04(s, 1H); IR(CHCl3)ν 1610, 1502, 1360, 1272, 1176cm-1.[α] D -19.77 (c 1, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.91 (ddd, J = 13.6, 7.5, 2.0 Hz, 1H), 2.14 (m, 1H), 2.63 (ddd, J = 13.5, 8.4, 2.3 Hz, 1H), 3.56 ( dd, J = 8.8, 7.7 Hz, 1H), 3.74 (m, 2H), 3.98 (dd, J = 8.9, 6.8 Hz, 1H), 4.31 (d, J = 14.3 Hz, 1H), 4.50 (d, J = 14.2 Hz, 1H), 6.80 (m, 2H), 7.34 (m, 3H), 7.65 (s, 1H), 7.67 (s, 1H), 7.81 (s, 1H), 8.04 (s, 1H); IR (CHCl 3 ) ν 1610, 1502, 1360, 1272, 1176 cm −1 .
화합물3b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 3b ' :
[α]D-50.04(c 0.5, CHCl3);1H-NMR(CDCl3)δ 2.01(m, 2H), 2.26(d, J=6.4Hz, 2H), 2.90(m, 1H), 3.57(t, J=8.6Hz, 1H), 4.08(m, 1H), 4.33(d, J=14.3Hz, 1H), 4.56(d, J=14.2Hz, 1H), 6.87(m, 2H), 7.48(m, 1H), 7.86(s, 1H), 8.08(s, 1H); IR(CHCl3)ν 2247, 1610cm-1.[α] D −50.04 (c 0.5, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 2.01 (m, 2H), 2.26 (d, J = 6.4 Hz, 2H), 2.90 (m, 1H), 3.57 (t, J = 8.6 Hz, 1H), 4.08 (m , 1H), 4.33 (d, J = 14.3 Hz, 1H), 4.56 (d, J = 14.2 Hz, 1H), 6.87 (m, 2H), 7.48 (m, 1H), 7.86 (s, 1H), 8.08 (s, 1 H); IR (CHCl 3 ) ν 2247, 1610 cm −1 .
단계 2:Step 2:
상기 단계 1에서 제조한 화합물3b'1g, 1M 농도의 디이소부틸알루미늄하이드라이드/톨루엔 용액 6ml와 톨루엔 16ml을 사용한 것을 제외하고는 실시예 1의 단계 2에서와 동일한 방법으로 (-)-(2R-트랜스)-2-(2,4-디플루오닐페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-4-(포밀메틸)테트라하이드로푸란(반응식1의 화합물5b중 Z1및 Z2가 모두 F인 경우)(이하5b'로 표시) 407mg을 제조하였다.(-)-(2R) in the same manner as in Step 2 of Example 1, except that 1 g of Compound 3b ' prepared in Step 1, 6 ml of diisobutylaluminum hydride / toluene solution at a concentration of 1M, and 16 ml of toluene were used. -Trans) -2- (2,4-difluoroylphenyl) -2- [1H- (1,2,4-triazol-1-yl) methyl] -4- (formylmethyl) tetrahydrofuran (Scheme) In the compound 5b of 1 , when Z 1 and Z 2 were both F) (hereinafter referred to as 5b ' ), 407 mg was prepared.
화합물5b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 5b ' :
[α]D-30.4(c 0.5, CHCl3);1H-NMR(CDCl3)δ 1.83(m, 1H), 2.16(m, 1H), 2.40(m, 2H), 3.39(t, J=8.8Hz, 1H), 4.20(dd, J=8.4, 6.9Hz, 1H), 4.36(d, J=14.2Hz, 1H), 4.54(d, J=14.2Hz, 1H), 6.84(m, 2H), 7.43(m, 1H), 7.84(s, 1H), 8.09(s, 1H), 9.64(br, 1H); IR(CHCl3)ν 2729, 1722 cm-1.[α] D -30.4 (c 0.5, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.83 (m, 1H), 2.16 (m, 1H), 2.40 (m, 2H), 3.39 (t, J = 8.8 Hz, 1H), 4.20 (dd, J = 8.4, 6.9 Hz, 1H), 4.36 (d, J = 14.2 Hz, 1H), 4.54 (d, J = 14.2 Hz, 1H), 6.84 (m, 2H), 7.43 (m, 1H), 7.84 (s, 1H) , 8.09 (s, 1 H), 9.64 (br, 1 H); IR (CHCl 3 ) ν 2729, 1722 cm −1 .
단계 3:Step 3:
실시예 1의 단계 3과 동일한 방법으로 디메틸-3-메틸-2-옥소부틸포스포네이트 245mg, 1,8-디아자바이싸이클로[5,4,0]-7-운데센 192mg과 리튬클로라이드 54mg, 아세토니트릴 11ml과 상기 단계 2에서 제조한5b'352mg을 사용하여 중간 생성물 364mg을 얻었으며, 이 중간 생성물 330mg, 5% 활성탄/팔라듐 촉매 40mg 및 무수 에탄올 15ml을 사용하여 수소환원 반응을 시켜 목적물인 상기 화학식 11의 화합물7b'266mg을 제조하였다.245 mg of dimethyl-3-methyl-2-oxobutylphosphonate, 192 mg of 1,8-diazabicyclo [5,4,0] -7-undecene and 54 mg of lithium chloride in the same manner as in step 3 of Example 1, 11 ml of acetonitrile and 352 mg of 5b ' prepared in step 2 were used to obtain 364 mg of an intermediate product. The intermediate product was subjected to hydrogen reduction using 330 mg, 40% of 5% activated carbon / palladium catalyst and 15 ml of anhydrous ethanol. 266 mg of compound 7b ' of Formula 11 was prepared.
화합물7b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 7b ' :
[α]D-26.64(c 0.5, CHCl3);1H-NMR(CDCl3)δ 1.04(s, 3H), 1.07(s, 3H), 1.16(m, 2H), 1.46(m, 2H), 1.74(m, 1H), 2.35(t, J=7.1Hz, 2H), 2.78(m, 1H), 3.33(m, 1H), 4.06(t, 1H), 4.30(d, J=14.1Hz, 1H), 4.54(d, J=14.1Hz, 1H), 6.84(m, 2H), 7.46(m, 1H), 7.86(s, 1H), 8.11(s, 1H); IR(CHCl3)ν 1708cm-1.[α] D -26.64 (c 0.5, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.04 (s, 3H), 1.07 (s, 3H), 1.16 (m, 2H), 1.46 (m, 2H), 1.74 (m, 1H), 2.35 (t, J = 7.1 Hz, 2H), 2.78 (m, 1H), 3.33 (m, 1H), 4.06 (t, 1H), 4.30 (d, J = 14.1 Hz, 1H), 4.54 (d, J = 14.1 Hz, 1H) 6.84 (m, 2 H), 7.46 (m, 1 H), 7.86 (s, 1 H), 8.11 (s, 1 H); IR (CHCl 3 ) ν 1708 cm −1 .
<실시예 3><Example 3>
(-)-(2R-시스)2-(2,4-디플루오로페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-4-(4-아미노-5-메틸헥실)테트라하이드로푸란의 제조(-)-(2R-cis) 2- (2,4-difluorophenyl) -2- [1H- (1,2,4-triazol-1-yl) methyl] -4- (4-amino Preparation of -5-methylhexyl) tetrahydrofuran
본 실시예에서 제조하고자 하는 화합물은 상기 화학식 12로 표시되는 화합물로서 반응식 1에서9a화합물 중 Z1및 Z2가 모두 F인 화합물(이하9a'로 표시)이다.The compound to be prepared in the present Example is a compound represented by Chemical Formula 12, wherein Z 1 and Z 2 in the 9a compound of Scheme 1 are both F (hereinafter, referred to as 9a ′ ).
상기 실시예 1에서 제조한 화합물7a'110.9mg, 하이드록실아민염산염 33mg및 피리딘 77㎕를 무수 에탄올 4ml에 용해시킨 후에 상온에서 하루 밤 동안 교반하였다. 이 반응액을 감압 농축하고, 에틸아세테이트에 희석시키고, 정제수로 세척하였다. 다음으로, 무수 마그네슘설페이트로 건조시키고, 불용성 물질을 여과하였다. 여액을 농축하여 얻은 잔사 95mg 중 63mg을 메탄올 2ml에 용해시키고, -30℃로 냉각시킨 후 니켈(II)클로라이드육수화물 76.6mg과 소디움보로하이드라이드 61mg을 가하였다.110.9 mg of Compound 7a ' prepared in Example 1, 33 mg of hydroxylamine hydrochloride, and 77 µl of pyridine were dissolved in 4 ml of anhydrous ethanol, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed with purified water. Next, it was dried over anhydrous magnesium sulfate and the insoluble substance was filtered off. 63 mg of 95 mg of the residue obtained by concentrating the filtrate was dissolved in 2 ml of methanol, cooled to −30 ° C., and 76.6 mg of nickel (II) chloride hexahydrate and 61 mg of sodium borohydride were added thereto.
이어서 -30℃에서 30분, 상온에서 90분 동안 교반한 후 반응액을 감압 농축하였다. 암갈색의 잔사를 10% 염산 1ml에 용해시킨 후 암모니아수를 가하여 중화시켰다. 에틸아세테이트로 희석하고 정제수로 세척한 후 무수 마그네슘설페이트로 건조시키고 불용성 물질을 여과하였다. 여액을 감액 농축하여 얻어진 잔사를 관 크로마토그래프로 분리하여 목적물인 상기 화학식 12의 화합물9a'54.3mg을 제조하였다.Subsequently, after stirring for 30 minutes at -30 ℃, 90 minutes at room temperature, the reaction solution was concentrated under reduced pressure. The dark brown residue was dissolved in 1 ml of 10% hydrochloric acid and neutralized by adding ammonia water. Diluted with ethyl acetate, washed with purified water, dried over anhydrous magnesium sulfate and filtered the insoluble material. The residue obtained by reducing the filtrate was concentrated by column chromatography to prepare 54.3 mg of the compound 9a ' of the formula 12 as a target.
화합물9a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 9a ' :
1H-NMR(CDCl3)δ 0.83(d, J=6.7Hz, 3H), 0.87(d, J=6.8Hz, 3H), 1.1- 1.4(m, 6H), 1.56(m, 1H), 1.69(m, 3H), 2.05(m, 2H), 2.47(m, 2H), 3.37(t, 1H), 4.10(t, J=7.8Hz, 1H), 4.50(d, J=14.2Hz, 1H), 4.61(d, J=14.3Hz, 1H), 6.82(m, 2H), 7.37(m, 1H), 7.81(s, 1H), 8.11(s, 1H); IR(CHCl3)ν 3376, 3308, 2918, 1611cm-1. 1 H-NMR (CDCl 3 ) δ 0.83 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 1.1- 1.4 (m, 6H), 1.56 (m, 1H), 1.69 (m, 3H), 2.05 (m, 2H), 2.47 (m, 2H), 3.37 (t, 1H), 4.10 (t, J = 7.8 Hz, 1H), 4.50 (d, J = 14.2 Hz, 1H) 4.61 (d, J = 14.3 Hz, 1H), 6.82 (m, 2H), 7.37 (m, 1H), 7.81 (s, 1H), 8.11 (s, 1H); IR (CHCl 3 ) ν 3376, 3308, 2918, 1611 cm −1 .
<실시예 4><Example 4>
(-)-(2R-트랜스)2-(2,4-디플루오로페닐)-2-[1H-(1,2,4-트리아졸-1-일)메틸]-4-(4-아미노-5-메틸헥실)테트라하이드로푸란의 제조(-)-(2R-trans) 2- (2,4-difluorophenyl) -2- [1H- (1,2,4-triazol-1-yl) methyl] -4- (4-amino Preparation of -5-methylhexyl) tetrahydrofuran
본 실시예에서 제조하고자 하는 화합물은 상기 화학식 13으로 표시되는 화합물로서 반응식 1에서9b화합물 중 Z1및 Z2가 모두 F인 화합물(이하9b'로 표시)이다.The compound to be prepared in the present example is a compound represented by Chemical Formula 13, wherein Z 1 and Z 2 in the 9b compound of Scheme 1 are both F (hereinafter referred to as 9b ′ ).
상기 실시예 3과 동일한 방법으로, 상기 실시예 2에서 제조한 화합물7b'173mg, 하이드록실아민염산염 50mg 및 피리딘 100㎕ 및 무수 에탄올 5ml를 사용하여 중간 생성물 165mg을 얻었다. 이 중간 생성물 111mg, 메틴올 4ml, 니켈(II)클로라이드육수화물 135mg과 소디움보로하이드라이드 107mg을 사용하여 목적물인 상기 화학식 13의 화합물9b'95mg을 제조하였다.In the same manner as in Example 3, 165 mg of an intermediate product was obtained using 173 mg of Compound 7b ′ , 50 mg of hydroxylamine hydrochloride, 100 μl of pyridine, and 5 ml of anhydrous ethanol. 111 mg of this intermediate product, 4 ml of methineol, 135 mg of nickel (II) chloride hexahydrate and 107 mg of sodium borohydride were used to prepare 95 mg of the compound 9b ' of the above formula (13).
화합물9b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 9b ' :
1H-NMR(CDCl3)δ 0.83(dd, J=6.8, 0.9Hz, 3H), 0.87(d, J=6.8Hz, 3H), 1.09- 1.36(m, 6H), 1.50-1.60(m, 4H), 1.73(m, 1H), 2.43(m, 1H), 2.78(m, 1H), 3.33(t, J=9.1Hz, 1H), 4.06(t, J=7.6Hz, 1H), 4.30(d, J=14.1Hz, 1H), 4.54(d, J=14.1Hz, 1H), 6.84(m, 2H), 7.47(m, 1H), 7.86(s, 1H), 8.11(s, 1H); IR(CHCl3)ν 3375, 3306, 2915, 1609cm-1. 1 H-NMR (CDCl 3 ) δ 0.83 (dd, J = 6.8, 0.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 1.09-1.36 (m, 6H), 1.50-1.60 (m, 4H), 1.73 (m, 1H), 2.43 (m, 1H), 2.78 (m, 1H), 3.33 (t, J = 9.1 Hz, 1H), 4.06 (t, J = 7.6 Hz, 1H), 4.30 ( d, J = 14.1 Hz, 1H), 4.54 (d, J = 14.1 Hz, 1H), 6.84 (m, 2H), 7.47 (m, 1H), 7.86 (s, 1H), 8.11 (s, 1H); IR (CHCl 3 ) ν 3375, 3306, 2915, 1609 cm −1 .
<실시예 5>Example 5
(-)-(2R-시스)-2-(2,4-디플루오로페닐)-2-[1H-(이미다졸-1-일)메틸]-4-(5-메틸-4-옥소헥실)테트라하이드로푸란의 제조(-)-(2R-cis) -2- (2,4-difluorophenyl) -2- [1H- (imidazol-1-yl) methyl] -4- (5-methyl-4-oxohexyl Preparation of Tetrahydrofuran
본 실시예에서 제조하고자 하는 화합물은 상기 화학식 14로 표시되는 화합물로서 반응식 2에서11a화합물 중 Z1및 Z2가 모두 F인 화합물(이하11a'로 표시)이다.The compound to be prepared in the present Example is a compound represented by Chemical Formula 14, wherein Z 1 and Z 2 in Compound 11a in Formula 2 are both F (hereinafter, referred to as 11a ′ ).
단계 1:Step 1:
화학적 특징이 다음과 같은 (-)-(2R-시스)-2-(2,4-디플루오닐페닐)-2-(벤질옥시메틸)-테트라하이드로-4-푸란메탄올,4-톨루엔설포네이트(반응식 2의 화합물2a중 Z가 F인 경우)(이하2a'로 표시) 1.44g, KCN 297mg과 디메틸설폭사이드 16ml을 사용한 것을 제외하고는 실시예 1의 단계 1에서와 동일한 방법을 사용하고, 관 크로마토그래프로 분리하여 (-)-(2R-시스)-2-(2,4-디플루오닐페닐)-2-(벤질옥시메틸) -4-(시아노메틸)테트라하이드로푸란(반응식2의 화합물4a중 Z1및 Z2가 모두 F인 경우)(이하4a'로 표시) 0.9g을 제조하였다.Chemical properties of (-)-(2R-cis) -2- (2,4-difluoroylphenyl) -2- (benzyloxymethyl) -tetrahydro-4-furanmethanol, 4-toluenesulfonate (When Z is F in compound 2a of Scheme 2) (hereinafter denoted as 2a ' ) 1.44 g, the same method as in step 1 of Example 1 was used except that 297 mg of KCN and 16 ml of dimethylsulfoxide were used, (-)-(2R-cis) -2- (2,4-difluoroylphenyl) -2- (benzyloxymethyl) -4- (cyanomethyl) tetrahydrofuran (Scheme 2) 0.9 g of the compound 4a when Z 1 and Z 2 were both F) (hereinafter referred to as 4a ' ) was prepared.
화합물2a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 2a ' :
녹는점 75-75.5℃; [α]D-12.0(c 0.9, CHCl3);1H-NMR(CDCl3)δ 2.11(dd, J=13.2, 6.6Hz, 1H), 2.28(ddd, J=13.2, 8.1, 2.4Hz, 1H), 2.42(s, 3H), 2.51(m, 1H), 3.53(dd, J=10.5, 1.8Hz, 1H), 3.79(dd, J=9, 5.4Hz, 1H), 3.89(dd, J=9.2, 6.9Hz, 1H), 4.0-4.12(m, 2H), 4.49(s, 2H), 6.7-6.77(m, 1H), 6.81-6.88(m, 1H), 7.17-7.21(m, 2H), 7.27-7.34(m, 5H), 7.48-7.56(m, 1H), 7.71-7.75(m, 2H); IR(CHCl3)ν 2865, 1615, 1598, 1497, 1363, 1270, 1177, 1098, 966cm-1.Melting point 75-75.5 ° C .; [α] D -12.0 (c 0.9, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 2.11 (dd, J = 13.2, 6.6 Hz, 1H), 2.28 (ddd, J = 13.2, 8.1, 2.4 Hz, 1H), 2.42 (s, 3H), 2.51 (m, 1H), 3.53 (dd, J = 10.5, 1.8 Hz, 1H), 3.79 (dd, J = 9, 5.4 Hz, 1H), 3.89 (dd, J = 9.2, 6.9 Hz, 1H), 4.0-4.12 (m , 2H), 4.49 (s, 2H), 6.7-6.77 (m, 1H), 6.81-6.88 (m, 1H), 7.17-7.21 (m, 2H), 7.27-7.34 (m, 5H), 7.48-7.56 (m, 1 H), 7.71-7.75 (m, 2 H); IR (CHCl 3 ) ν 2865, 1615, 1598, 1497, 1363, 1270, 1177, 1098, 966 cm −1 .
화합물4a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 4a ' :
[α]D-2.8(c 1.2, CHCl3);1H-NMR(CDCl3)δ 2.30-2.45(m, 2H), 2.50-2.60(m, 3H), 3.55(dd, J=10.5, 1.8Hz, 1H), 3.68(dd, J=10.5, 1.8Hz, 1H), 3.82(dd, J=8.7, 4.2Hz, 1H), 3.93-3.98(m, 1H), 4.57(s, 2H), 6.73-6.81(m, 1H), 6.83-6.90(m, 1H), 7.24-7.37(m, 5H), 7.52-7.60(m, 1H); IR(CHCl3)ν 3065, 2939, 2865, 2247, 1615, 1599, 1497, 1422, 1270, 1104, 1040cm-1.[α] D −2.8 (c 1.2, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 2.30-2.45 (m, 2H), 2.50-2.60 (m, 3H), 3.55 (dd, J = 10.5, 1.8 Hz, 1H), 3.68 (dd, J = 10.5, 1.8 Hz, 1H), 3.82 (dd, J = 8.7, 4.2 Hz, 1H), 3.93-3.98 (m, 1H), 4.57 (s, 2H), 6.73-6.81 (m, 1H), 6.83-6.90 (m, 1H), 7.24-7.37 (m, 5H), 7.52-7.60 (m, 1H); IR (CHCl 3 ) ν 3065, 2939, 2865, 2247, 1615, 1599, 1497, 1422, 1270, 1104, 1040 cm −1 .
단계 2:Step 2:
상기 단계 1에서 제조한 화합물4a'863mg, 1M 농도의 디이소부틸알루미늄하이드라이드/톨루엔 용액 3.3ml와 톨루엔 13ml을 사용한 것을 제외하고는 실시예 1의 단계 2에서와 동일한 방법으로 (-)-(2R-시스)-2-(2,4-디플루오닐페닐)-2-(벤질옥시메틸)-4-(포밀메틸)테트라하이드로푸란(반응식 2의 화합물6a중 Z1및 Z2가 모두 F인 경우)(이하6a'로 표시) 557mg을 제조하였다.Except for using the compound 4a ' 863mg prepared in step 1, 3.3ml of diisobutylaluminum hydride / toluene solution at a concentration of 1M and 13ml of toluene, (-)-( 2R-cis) -2- (2,4-difluoroylphenyl) -2- (benzyloxymethyl) -4- (formylmethyl) tetrahydrofuran (Z 1 and Z 2 in compound 6a of Scheme 2 are both F In the case of) (hereinafter referred to as 6a ' ) 557 mg was prepared.
화합물6a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 6a ' :
[α]D2.54(c 1.36, CHCl3);1H-NMR(CDCl3)δ 2.04(dd, J=12.8, 8.4Hz, 1H), 2.42(ddd, J=12.6, 6.9, 2.4Hz, 1H), 2.50-2.74(m, 3H), 4.16(dd, J=8.4, 6.6Hz, 1H), 4.55(s, 2H), 6.71-6.79(m, 1H), 6.84-6.90(m, 1H), 7.21-7.34(m, 5H), 7.55-7.64(m, 1H), 9.71(s, 1H); IR(CHCl3)ν 2941, 2862, 2723, 1723, 1600, 1497,1420, 1269, 1106, 1031, 965cm-1.[α] D 2.54 (c 1.36, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 2.04 (dd, J = 12.8, 8.4 Hz, 1H), 2.42 (ddd, J = 12.6, 6.9, 2.4 Hz, 1H), 2.50-2.74 (m, 3H), 4.16 ( dd, J = 8.4, 6.6 Hz, 1H), 4.55 (s, 2H), 6.71-6.79 (m, 1H), 6.84-6.90 (m, 1H), 7.21-7.34 (m, 5H), 7.55-7.64 ( m, 1 H), 9.71 (s, 1 H); IR (CHCl 3 ) ν 2941, 2862, 2723, 1723, 1600, 1497,1420, 1269, 1106, 1031, 965 cm -1 .
단계 3:Step 3:
상기 실시예 1의 단계 3과 동일한 방법으로 디메틸-3-메틸-2-옥소부틸포스포네이트 355mg, 1,8-디아자바이싸이클로 [5,4,0]-7-운데센 279mg과 리튬클로라이드 78mg, 아세토니트릴 15ml과 상기 단계2의6a'527mg을 사용하여 중간 생성물 560mg을 얻었으며, 이 중간 생성물 486mg, 5% 활성탄/팔라듐 촉매 48mg 및 무수 에탄올 20ml을 사용하여 수소환원 반응을 시켜 (-)-(2R-시스)2-(2,4-디플루오로페닐)-2-(하이드록시메틸)-4-(5-메틸-4-옥소헥실)테트라하이드로푸란(반응식 2의 화합물8a중 Z1및 Z2가 모두 F인 경우)(이하8a'로 표시) 362mg을 제조하였다.355 mg of dimethyl-3-methyl-2-oxobutylphosphonate, 279 mg of 1,8-diazabicycle [5,4,0] -7-undecene and 78 mg of lithium chloride in the same manner as in Step 3 of Example 1 , 15 ml of acetonitrile and 527 mg of 6a ' of step 2 were used to obtain 560 mg of an intermediate product, which was subjected to hydrogen reduction using 486 mg of this intermediate product, 48 mg of 5% activated carbon / palladium catalyst and 20 ml of anhydrous ethanol (-)- (2R-cis) 2- (2,4-difluorophenyl) -2- (hydroxymethyl) -4- (5-methyl-4-oxohexyl) tetrahydrofuran (Z 1 in compound 8a of Scheme 2) And 362 mg when both Z 2 are F) (hereinafter referred to as 8a ' ).
화합물8a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 8a ' :
[α]D-10.76(c 1.49, CHCl3);1H-NMR(CDCl3)δ 1.07(d, J=6.9Hz, 6H), 1.34-1.44(m, 2H), 1.46-1.59(m, 2H), 1.94(dd, J=12.2, 10.5Hz, 1H), 2.04-2.15(m, 2H), 2.33(ddd, J=11.9, 6.9, 2.4Hz, 1H), 2.43(t, J=6.9Hz, 2H), 2.56(sept, J=6.9Hz, 1H), 3.56(t, J=8.4Hz, 1H), 3.70(ddd, J=11.6, 5.4, 1.2Hz, 1H), 3.80(ddd, J=11.6, 8.3, 2.1Hz, 1H), 4.14(t, J=8.1Hz, 1H), 6.74-6.82(m, 1H), 6.83-6.89(m, 1H), 7.46-7.54(m, 1H); IR(CDCl3)ν 3466, 2969, 2933, 2871, 1709, 1614, 1601, 1497, 1269, 1136, 967cm-1.[α] D -10.76 (c 1.49, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.07 (d, J = 6.9 Hz, 6H), 1.34-1.44 (m, 2H), 1.46-1.59 (m, 2H), 1.94 (dd, J = 12.2, 10.5 Hz, 1H), 2.04-2.15 (m, 2H), 2.33 (ddd, J = 11.9, 6.9, 2.4 Hz, 1H), 2.43 (t, J = 6.9 Hz, 2H), 2.56 (sept, J = 6.9 Hz, 1H ), 3.56 (t, J = 8.4 Hz, 1H), 3.70 (ddd, J = 11.6, 5.4, 1.2 Hz, 1H), 3.80 (ddd, J = 11.6, 8.3, 2.1 Hz, 1H), 4.14 (t, J = 8.1 Hz, 1H), 6.74-6.82 (m, 1H), 6.83-6.89 (m, 1H), 7.46-7.54 (m, 1H); IR (CDCl 3 ) ν 3466, 2969, 2933, 2871, 1709, 1614, 1601, 1497, 1269, 1136, 967 cm −1 .
단계 4:Step 4:
상기 단계 3에서 제조한 화합물8a'158mg, N,N-디메틸아미노피리딘 6mg과 트리에틸아민 0.14ml을 디클로로메탄 3ml에 녹이고 빙수욕에서 냉각시켰다. 상기 용액에 p-톨루엔설포닐클로라이드 138mg을 가하고 상온하여 7시간 동안 교반한 후 반응액을 에틸아세테이트로 희석하고, 정제수, 5% 구연산수 및 소금수로 세척하였다. 다음으로 무수 마그네슘설페이트로 건조시키고 불용성 물질을 여과하였다. 이어서, 여액을 감압 농축하여 얻어진 잔사를 관크로마토그래프로 분리하여 (-)-(2R-시스)-2-(2,4-디플루오로페닐)-4-(5-메틸-4-옥소헥실)테트라하이드로-2-푸란메탄올,4-톨루엔설포네이트(반응식 2의 화합물10a중 Z1및 Z2가 모두 F인 경우)(이하10a'로 표시) 228mg을 제조하였다.158 mg of the compound 8a ' prepared in Step 3, 6 mg of N, N-dimethylaminopyridine, and 0.14 ml of triethylamine were dissolved in 3 ml of dichloromethane and cooled in an ice water bath. 138 mg of p-toluenesulfonyl chloride was added to the solution, followed by stirring at room temperature for 7 hours, and then the reaction solution was diluted with ethyl acetate and washed with purified water, 5% citric acid and brine. Next, it was dried over anhydrous magnesium sulfate and the insoluble substance was filtered out. Subsequently, the residue obtained by concentrating the filtrate under reduced pressure was separated by a column chromatography, and (-)-(2R-cis) -2- (2,4-difluorophenyl) -4- (5-methyl-4-oxohexyl 228 mg of tetrahydro-2-furanmethanol, 4-toluenesulfonate (when Z 1 and Z 2 in compound 10a of Scheme 2 are both F) (hereinafter referred to as 10a ' ) was prepared.
화합물10a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 10a ' :
[α]D-8.38(c 1.03, CHCl3);1H-NMR(CDCl3)δ1.07(d, J=6.9Hz, 6H), 1.29-1.24(m, 2H), 1.40-1.55(m, 2H), 1.84(dd, J=12.5, 10.2Hz, 1H), 1.96-2.10(m, 1H), 2.31(ddd, J=12.4, 7.2, 2.7Hz, 1H), 2.39-2.44(m, 5H), 2.56(Sept, J=6.9Hz, 1H), 3.51(t, J=8.4Hz, 1H), 4.05(t, J=7.8Hz, 1H), 4.16(dd, J=10.5, 0.9Hz, 1H), 4.24(d, J=10.5Hz, 1H), 6.62-6.69(m, 1H), 6.79-6.85(m, 1H), 7.27-7.29(m, 1H), 7.44-7.52(m, 1H), 7.64-7.67(m, 2H); IR(CHCl3)ν 2970, 2934, 2872, 1711, 1615, 1599, 1498, 1363, 1177, 968cm-1.[α] D -8.38 (c 1.03, CHC1 3 ); 1 H-NMR (CDCl 3 ) δ1.07 (d, J = 6.9 Hz, 6H), 1.29-1.24 (m, 2H), 1.40-1.55 (m, 2H), 1.84 (dd, J = 12.5, 10.2 Hz , 1H), 1.96-2.10 (m, 1H), 2.31 (ddd, J = 12.4, 7.2, 2.7 Hz, 1H), 2.39-2.44 (m, 5H), 2.56 (Sept, J = 6.9 Hz, 1H), 3.51 (t, J = 8.4 Hz, 1H), 4.05 (t, J = 7.8 Hz, 1H), 4.16 (dd, J = 10.5, 0.9 Hz, 1H), 4.24 (d, J = 10.5 Hz, 1H), 6.62-6.69 (m, 1 H), 6.79-6.85 (m, 1 H), 7.27-7.29 (m, 1 H), 7.44-7.52 (m, 1 H), 7.64-7.67 (m, 2H); IR (CHCl 3 ) ν 2970, 2934, 2872, 1711, 1615, 1599, 1498, 1363, 1177, 968 cm −1 .
단계 5:Step 5:
상기 단계 4에서 제조한 화합물10a'183mg과 소디움이미다졸 90mg을 N,N'-디메틸프로필렌우레아 3ml에 용해시킨 후에 100℃에서 44시간 동안 교반하였다. 이 반응액을 에틸아세테이트로 희석하고, 정세수로 세척한 다음 무수 마그네슘설페이트로 건조시키고 불용성 물질을 여과하였다. 여액을 감압 농축하여 얻어진 잔사를 관 크로마토그래프로 분리하여 목적물인 상기 화학식 14의 화합물11a'40mg을 제조하였다.183 mg of Compound 10a ' prepared in Step 4 and 90 mg of sodium imidazole were dissolved in 3 ml of N, N'-dimethylpropylene urea, followed by stirring at 100 ° C. for 44 hours. The reaction solution was diluted with ethyl acetate, washed with purified water, dried over anhydrous magnesium sulfate, and the insoluble substance was filtered out. The residue obtained by concentrating the filtrate under reduced pressure was separated by a column chromatograph to prepare 40 mg of compound 11a ' of Chemical Formula 14 as a target.
화합물11a'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 11a ' :
[α]D-31.71(c 0.1, CHCl3);1H-NMR(CDCl3)δ1.06(d, J=6.9Hz, 6H), 1.16-1.27(m, 2H), 1.35-1.52(m, 2H), 1.55(dd, J=12.5, 10.8Hz, 1H), 1.98-2.10(m, 1H), 2.36-2.46(m, 3H), 2.54(Sept, J=6.9Hz, 1H), 3.44(t, J=9Hz, 1H), 4.09(t, J=8.1Hz, 1H), 4.24(dd, J=17.1, 14.4Hz, 2H), 6.76-6.85(m, 2H), 6.86(s, 1H), 6.92(s, 1H), 7.32-7.40(m, 2H), 7.64-7.67(m, 2H); IR(CHCl3)ν 2970, 2935, 2871, 1710, 1615, 1600, 1498, 1269, 1136, 1076, 965cm-1.[α] D -31.71 (c 0.1, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ1.06 (d, J = 6.9 Hz, 6H), 1.16-1.27 (m, 2H), 1.35-1.52 (m, 2H), 1.55 (dd, J = 12.5, 10.8 Hz , 1H), 1.98-2.10 (m, 1H), 2.36-2.46 (m, 3H), 2.54 (Sept, J = 6.9 Hz, 1H), 3.44 (t, J = 9 Hz, 1H), 4.09 (t, J = 8.1 Hz, 1H), 4.24 (dd, J = 17.1, 14.4 Hz, 2H), 6.76-6.85 (m, 2H), 6.86 (s, 1H), 6.92 (s, 1H), 7.32-7.40 (m, 2H), 7.64-7.67 (m, 2H); IR (CHCl 3 ) ν 2970, 2935, 2871, 1710, 1615, 1600, 1498, 1269, 1136, 1076, 965 cm -1 .
<실시예 6><Example 6>
(-)-(2R-트랜스)-2-(2,4-디플루오로페닐)-2-[1H-(이미다졸-1-일)메틸]-4-(5-메틸-4-옥소헥실)테트라하이드로푸란의 제조(-)-(2R-trans) -2- (2,4-difluorophenyl) -2- [1H- (imidazol-1-yl) methyl] -4- (5-methyl-4-oxohexyl Preparation of Tetrahydrofuran
본 실시예에서 제조하고자 하는 화합물은 상기 화학식 15로 표시되는 화합물로서 반응식 2에서11b화합물 중 Z1및 Z2가 모두 F인 화합물(이하11b'로 표시)이다.The compound to be prepared in the present Example is a compound represented by Chemical Formula 15, wherein Z 1 and Z 2 in Compound 11b in Formula 2 are both F (hereinafter referred to as 11b ′ ).
단계 1:Step 1:
화학적 특징이 다음과 같은 (-)-(2R-트랜스)-2-(2,4-디플루오닐페닐)-2-(벤질옥시메틸)-테트라하이드로-4-푸란메탄올-4-톨루엔설포네이트(반응식 2의 화합물2b중 Z가 F인 경우)(이하2b'로 표시) 2.41g, KCN 440mg과 디메틸설폭사이드 23ml을 사용한 것을 제외하고는 실시예 1의 단계 1에서와 동일한 방법을 사용하고, 관 크로마토그래프로 분리하여 (-)-(2R-트랜스)-2-(2,4-디플루오닐페닐)-2-(벤질옥시메틸)-4-(시아노메틸)테트라하이드로푸란(반응식2의 화합물4b중 Z1및 Z2가 모두 F인 경우)(이하4b'로 표시) 1.43g을 제조하였다.(-)-(2R-trans) -2- (2,4-difluoroylphenyl) -2- (benzyloxymethyl) -tetrahydro-4-furanmethanol-4-toluenesulfonate (When Z in the compound 2b of Scheme 2b is F) (hereinafter referred to as 2b ' ) Using the same method as in step 1 of Example 1, except that 2.41g, 440mg KCN and 23ml dimethylsulfoxide were used, Separation by column chromatography (-)-(2R-trans) -2- (2,4-difluoroylphenyl) -2- (benzyloxymethyl) -4- (cyanomethyl) tetrahydrofuran (Scheme 2 in the case of the compound 4b of Z 1 and Z 2 are both F) (hereinafter represented by 4b ') was prepared in 1.43g.
화합물2b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 2b ' :
[α]D16.5(c 1.0, CHCl3);1H-NMR(CDCl3)δ 1.77(ddd, J=13.2, 6.6, 2.1Hz, 1H), 2.44(s, 3H), 2.57(ddd, J=13.2, 8.4, 2.7Hz, 1H), 2.81(m, 1H), 3.47(dd, J=10.2, 1.8Hz, 1H), 3.58-3.63(m, 2H), 3.73-3.86(m, 2H), 4.15(dd, J=9, 6.9Hz, 1H), 4.50(s, 2H), 6.67-6.74(m, 1H), 6.77-6.83(m, 1H), 7.18-7.21(m, 2H), 7.24-7.33(m, 5H), 7.47-7.55(m, 1H), 7.67-7.72(m, 2H); IR(CHCl3)ν 2952, 2864, 1615, 1599, 1498, 1363, 1269, 1177, 1099, 967cm-1.[α] D 16.5 (c 1.0, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.77 (ddd, J = 13.2, 6.6, 2.1 Hz, 1H), 2.44 (s, 3H), 2.57 (ddd, J = 13.2, 8.4, 2.7 Hz, 1H), 2.81 ( m, 1H), 3.47 (dd, J = 10.2, 1.8 Hz, 1H), 3.58-3.63 (m, 2H), 3.73-3.86 (m, 2H), 4.15 (dd, J = 9, 6.9 Hz, 1H) , 4.50 (s, 2H), 6.67-6.74 (m, 1H), 6.77-6.83 (m, 1H), 7.18-7.21 (m, 2H), 7.24-7.33 (m, 5H), 7.47-7.55 (m, 1H), 7.67-7.72 (m, 2H); IR (CHCl 3 ) ν 2952, 2864, 1615, 1599, 1498, 1363, 1269, 1177, 1099, 967 cm −1 .
화합물4b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 4b ' :
[α]D19.0(c 1.2, CHCl3);1H-NMR(CDCl3)δ 1.86-1.95(m, 1H), 2.30(d,J=6.9Hz, 2H), 2.76-2.87(m, 2H), 3.49(dd, J=10.5, 1.5Hz, 1H), 3.62(dd, J=8.4, 6.9Hz, 1H), 3.65(dd, J=10.5, 1.5Hz, 1H), 4.24-4.29(m, 1H), 4.54(s, 2H), 6.73-6.80(m, 1H), 6.84-6.90(m, 1H), 7.22-7.35(m, 5H), 7.59-7.67(m, 1H); IR(CHCl3)ν 3064, 2944, 2863, 2247, 1615, 1600, 1499, 1423, 1269, 1106cm-1.[α] D 19.0 (c1 .2, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.86-1.95 (m, 1H), 2.30 (d, J = 6.9 Hz, 2H), 2.76-2.87 (m, 2H), 3.49 (dd, J = 10.5, 1.5 Hz, 1H), 3.62 (dd, J = 8.4, 6.9 Hz, 1H), 3.65 (dd, J = 10.5, 1.5 Hz, 1H), 4.24-4.29 (m, 1H), 4.54 (s, 2H), 6.73-6.80 (m, 1 H), 6.84-6.90 (m, 1 H), 7.22-7.35 (m, 5 H), 7.59-7.67 (m, 1 H); IR (CHCl 3 ) ν 3064, 2944, 2863, 2247, 1615, 1600, 1499, 1423, 1269, 1106 cm −1 .
단계 2:Step 2:
상기 단계 1에서 제조한 화합물4b'1.23g, 1M 농도의 디이소부틸알루미늄하이드라이드/톨루엔 용액 4.7ml와 톨루엔 18ml을 사용한 것을 제외하고는 실시예 1의 단계 2에서와 동일한 방법으로 (-)-(2R-트랜스)-2-(2,4-디플루오닐페닐)-2-(벤질옥시메틸)-4-(포밀메틸)테트라하이드로푸란(반응식 2의 화합물6b중 Z1및 Z2가 모두 F인 경우)(이하6b'로 표시) 918mg을 제조하였다.In the same manner as in Step 2 of Example 1, except that 1.23 g of Compound 4b ′ prepared in Step 1, 4.7 ml of 1M diisobutylaluminum hydride / toluene solution, and 18 ml of toluene were used. (2R-trans) -2- (2,4-difluoroylphenyl) -2- (benzyloxymethyl) -4- (formylmethyl) tetrahydrofuran (Z 1 and Z 2 in compound 6b of Scheme 2 are both In case of F) (hereinafter referred to as 6b ' ), 918 mg was prepared.
화합물 6b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 6b ':
[α]D13.8(c 0.9, CHCl3);1H-NMR(CDCl3)δ 1.74(ddd, J=12.9, 8.4, 2.4Hz, 1H), 2.36-2.52(m, 2H), 2.70-2.80(m, 1H), 2.84-2.97(m, 1H), 3.44(t, J=8.4Hz, 1H), 3.53(dd, J=10.5, 1.5Hz, 1H), 3.65(dd, J=10.2, 1.5Hz, 1H), 4.31(dd, J=8.1, 6.9Hz, 1H), 4.54(s, 2H), 6.71-6.79(m, 1H), 6.83-6.90(m, 1H), 7.20-7.33(m, 5H), 7.60-7.68(m, 1H), 9.71(t, J=1.5Hz, 1H); IR(CHCl3)ν 2944, 2860, 2724, 1723, 1615, 1600, 1497, 1421, 1269, 1104, 965cm-1.[α] D 13.8 (c 0.9, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.74 (ddd, J = 12.9, 8.4, 2.4 Hz, 1H), 2.36-2.52 (m, 2H), 2.70-2.80 (m, 1H), 2.84-2.97 (m, 1H ), 3.44 (t, J = 8.4 Hz, 1H), 3.53 (dd, J = 10.5, 1.5 Hz, 1H), 3.65 (dd, J = 10.2, 1.5 Hz, 1H), 4.31 (dd, J = 8.1, 6.9 Hz, 1H), 4.54 (s, 2H), 6.71-6.79 (m, 1H), 6.83-6.90 (m, 1H), 7.20-7.33 (m, 5H), 7.60-7.68 (m, 1H), 9.71 (t, J = 1.5 Hz, 1 H); IR (CHCl 3 ) ν 2944, 2860, 2724, 1723, 1615, 1600, 1497, 1421, 1269, 1104, 965 cm -1 .
단계 3:Step 3:
상기 실시예 1의 단계 3과 동일한 방법으로 디메틸-3-메틸-2-옥소부틸포스포네이트 523mg, 1,8-디아자바이싸이클로[5,4,0]-7-운데센 417mg과 리튬클로라이드 114mg, 아세토니트릴 24ml과 상기 단계2의6b'847mg을 사용하여 중간 생성물 782mg을 얻었으며, 이 중간 생성물 778mg, 5% 활성탄/팔라듐 촉매 77mg 및 무수 에탄올 30ml을 사용하여 수소환원 반응을 시켜 (-)-(2R-트랜스)2-(2,4-디플루오로페닐)-2-(하이드록시메틸)-4-(5-메틸-4-옥소헥실)테트라하이드로푸란(반응식 2의 화합물8b중 Z1및 Z2가 모두 F인 경우)(이하8b'로 표시) 568mg을 제조하였다.523 mg of dimethyl-3-methyl-2-oxobutylphosphonate, 417 mg of 1,8-diazabicyclo [5,4,0] -7-undecene and 114 mg of lithium chloride in the same manner as in Step 3 of Example 1 , 24 ml of acetonitrile and 847 mg of 6b ' of step 2 to obtain 782 mg of an intermediate product, which was subjected to hydrogen reduction using 778 mg of this intermediate product, 77 mg of 5% activated carbon / palladium catalyst and 30 ml of anhydrous ethanol (-)- (2R-trans) 2- (2,4-difluorophenyl) -2- (hydroxymethyl) -4- (5-methyl-4-oxohexyl) tetrahydrofuran (Z 1 in compound 8b of Scheme 2) And 568 mg when Z 2 are all F) (hereinafter referred to as 8b ' ).
화합물8b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 8b ' :
[α]D-7.83(c 1.19, CHCl3);1H-NMR(CDCl3)δ 1.07(d, J=7.2Hz, 6H), 1.26(dd, J=15.8, 8.1Hz, 2H), 1.49-1.60(m, 2H), 1.71(ddd, J=12.9, 9.3, 2.1Hz, 1H), 2.21(dd, J=7.2, 6.6Hz, 1H), 2.31-2.44(m, 3H), 2.55(dd, J=13.8, 6.9Hz, 1H), 2.60-2.69(m, 1H), 3.40(dd, J=9.3, 8.4Hz, 1H), 3.60(ddd, J=11.5, 6, 1.2Hz, 1H), 3.70(ddd, J=11.3, 7.8, 1.5Hz, 1H), 4.16(t, J=8.1Hz, 1H), 6.78-6.85(m, 2H), 7.51-7.59(m, 1H); IR(CHCl3)ν 3464, 2969, 2937, 2871, 1710, 1615, 1600, 1497, 1421, 1269, 1135, 1056, 967cm-1.[α] D -7.83 (c 1.19, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ 1.07 (d, J = 7.2 Hz, 6H), 1.26 (dd, J = 15.8, 8.1 Hz, 2H), 1.49-1.60 (m, 2H), 1.71 (ddd, J = 12.9, 9.3, 2.1 Hz, 1H), 2.21 (dd, J = 7.2, 6.6 Hz, 1H), 2.31-2.44 (m, 3H), 2.55 (dd, J = 13.8, 6.9 Hz, 1H), 2.60-2.69 (m, 1H), 3.40 (dd, J = 9.3, 8.4 Hz, 1H), 3.60 (ddd, J = 11.5, 6, 1.2 Hz, 1H), 3.70 (ddd, J = 11.3, 7.8, 1.5 Hz, 1H ), 4.16 (t, J = 8.1 Hz, 1H), 6.78-6.85 (m, 2H), 7.51-7.59 (m, 1H); IR (CHCl 3 ) ν 3464, 2969, 2937, 2871, 1710, 1615, 1600, 1497, 1421, 1269, 1135, 1056, 967 cm −1 .
단계 4:Step 4:
상기 단계 3에서 제조한 화합물 8b' 142mg, N,N-디메틸아미노피리딘 5.3mg과 트리에틸아민 0.12ml, 디클로로메탄 3ml와 p-톨루엔설포닐클로라이드 124mg을 사용한 것을 제외하고는 상기 실시예 5의 단계 4에서와 동일한 방법으로 (-)-(2R-트랜스)-2-(2,4-디플루오로페닐)-4-(5-메틸-4-옥소헥실)테트라하이드로-2-푸란메탄올,4-톨루엔설포네이트(반응식 2의 화합물10b중 Z1및 Z2가 모두 F인 경우)(이하10b'로 표시) 205mg을 제조하였다.Example 5 except that 142 mg of compound 8b ′ prepared in step 3, 5.3 mg of N, N-dimethylaminopyridine, 0.12 ml of triethylamine, 3 ml of dichloromethane and 124 mg of p-toluenesulfonylchloride were used. (-)-(2R-trans) -2- (2,4-difluorophenyl) -4- (5-methyl-4-oxohexyl) tetrahydro-2-furanmethanol in the same manner as in 4,4 205 mg of toluenesulfonate (when Z 1 and Z 2 in compound 10b of Scheme 2 are both F) (hereinafter referred to as 10b ' ) was prepared.
화합물10b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 10b ' :
[α]D-5.74(c 1.03, CHCl3);1H-NMR(CDCl3)δ1.06(d, J=6.9Hz, 6H), 1.18-1.28(m, 2H), 1.45-1.57(m, 21), 1.62-1.70(m, 1H), 2.30-2.44(m, 6H), 2.50-2.65(m, 2H), 3.34(dd, J=9.2, 8.46Hz, 1H), 4.0(dd, J=10.1, 0.9Hz, 1H), 4.08(t, J=7.5Hz, 1H), 4.16(dd, J=10.2, 0.6Hz, 1H), 6.64-6.71(m, 1H), 6.78-6.85(m, 1H), 7.28-7.31(m, 1H), 7.48-7.57(m, 1H), 7.65-7.69(m, 2H); IR(CHCl3)ν 2969, 2939, 2871, 1710, 1615, 1598, 1498, 1363, 1177, 966cm-1.[α] D −5.74 (c 1.03, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ1.06 (d, J = 6.9 Hz, 6H), 1.18-1.28 (m, 2H), 1.45-1.57 (m, 21), 1.62-1.70 (m, 1H), 2.30 -2.44 (m, 6H), 2.50-2.65 (m, 2H), 3.34 (dd, J = 9.2, 8.46 Hz, 1H), 4.0 (dd, J = 10.1, 0.9 Hz, 1H), 4.08 (t, J = 7.5 Hz, 1H), 4.16 (dd, J = 10.2, 0.6 Hz, 1H), 6.64-6.71 (m, 1H), 6.78-6.85 (m, 1H), 7.28-7.31 (m, 1H), 7.48- 7.57 (m, 1 H), 7.65-7.69 (m, 2 H); IR (CHCl 3 ) ν 2969, 2939, 2871, 1710, 1615, 1598, 1498, 1363, 1177, 966 cm −1 .
단계 5:Step 5:
상기 단계 4에서 제조한 화합물10b'200mg과 소디움이미다졸 93mg을 N,N'-디메틸프로필렌우레아 3ml를 사용하여 상기 실시예 5의 단계 5와 동일한 방법으로 적물인 상기 화학식 15의 화합물11b'51mg을 제조하였다.Compound 11b ' 51mg of the compound of Formula 15, which is a product of step 10 of Example 5, using 200 ml of compound 10b' prepared in step 4 and 93 mg of sodium imidazole, using 3 ml of N, N'-dimethylpropylene urea Was prepared.
화합물11b'의 화학적 특징의 요약:Summary of Chemical Properties of Compound 11b ' :
[α]D-20.0(c 0.1, CHCl3);1H-NMR(CDCl3)δ1.05(d, J=6.9Hz, 6H), 1.11-1.19(m, 2H), 1.36-1.54(m, 2H), 1.61-1.79(m, 2H), 2.34(t, J=7.2Hz, 1H), 2.46-2.58(m, 2H), 3.34(t, J=9.3Hz, 1H), 4.04-4.19(m, 3H), 6.77-6.85(m, 2H), 6.87(s, 1H), 6.95(s, 1H), 7.40(s, 1H), 7.42-7.49(m, 1H); IR(CHCl3)ν 2969, 2938, 2870, 1709, 1616, 1598, 1499, 1269, 1107, 964cm-1.[α] D -20.0 (c 0.1, CHCl 3 ); 1 H-NMR (CDCl 3 ) δ1.05 (d, J = 6.9 Hz, 6H), 1.11-1.19 (m, 2H), 1.36-1.54 (m, 2H), 1.61-1.79 (m, 2H), 2.34 (t, J = 7.2 Hz, 1H), 2.46-2.58 (m, 2H), 3.34 (t, J = 9.3 Hz, 1H), 4.04-4.19 (m, 3H), 6.77-6.85 (m, 2H), 6.87 (s, 1 H), 6.95 (s, 1 H), 7.40 (s, 1 H), 7.42-7.49 (m, 1 H); IR (CHCl 3 ) ν 2969, 2938, 2870, 1709, 1616, 1598, 1499, 1269, 1107, 964 cm −1 .
<실시예 7><Example 7>
(-)-(2R-시스)-2-(2,4-디플루오로페닐)-2-[1H-(이미다졸-1-일)메틸]-4-(4-아미노-5-메틸헥실)테트라하이드로푸란의 제조(-)-(2R-cis) -2- (2,4-difluorophenyl) -2- [1H- (imidazol-1-yl) methyl] -4- (4-amino-5-methylhexyl Preparation of Tetrahydrofuran
본 실시예에서 제조하고자 하는 화합물은 상기 화학식 16으로 표시되는 화합물로서 반응식 2에서12a화합물 중 Z1및 Z2가 모두 F인 화합물(이하12a'로 표시)이다.The compound to be prepared in the present Example is a compound represented by Chemical Formula 16, wherein Z 1 and Z 2 in the 12a compound of Scheme 2 are both F (hereinafter referred to as 12a ′ ).
상기 실시예 3과 동일한 방법으로 실시예 5에서 제조한 화합물11a'34mg, 하이드록실아민염산염 11mg, 피리단 25㎕ 및 무수 에탄올 2ml을 사용하여 중간 생성물 34mg을 얻었다. 이 중간 생성물 34mg, 메탄올 2.5ml 및 니켈(II)클로라이드육수화물 41mg 및 소디움보로하이드라이드 33mg을 사용하여 목적물인 상기 화학식 16의 화합물12a'21mg을 제조하였다.In the same manner as in Example 3, 34 mg of the compound 11a ' prepared in Example 5, 11 mg of hydroxylamine hydrochloride, 25 µl of pyridan, and 2 ml of anhydrous ethanol were used to obtain 34 mg of an intermediate product. 34 mg of this intermediate product, 2.5 ml of methanol, 41 mg of nickel (II) chloride hexahydrate and 33 mg of sodium borohydride were used to prepare 21 mg of compound 12a ' of the above formula (16).
화합물 12a'의 화학적 특징 요약:Summary of Chemical Properties of Compound 12a ':
1H-NMR(CDCl3)δ 0.83(dd, J=6.9, 0.6Hz, 3H), 0.87(d, J=6.9Hz, 3H), 1.10-1.22(m, 2H), 1.26-1.36(m, 4H), 1.49-1.60(m, 4H), 2.02-2.09(m, 1H), 2.37-2.45(m, 2H), 3.43(t, J=9Hz, 1H), 4.09(t, J=7.8Hz, 1H), 4.24(dd, J=16.2, 15Hz,2H), 6.76-6.84(m, 2H), 6.86(t, J=1.2Hz, 1H), 6.92(t, J=1.2Hz, 1H), 7.32-7.41(m, 2H); IR(CHCl3)ν 3373, 3301, 2931, 2867, 1615, 1599, 1498, 1269, 1107, 1076, 965cm-1. 1 H-NMR (CDCl 3 ) δ 0.83 (dd, J = 6.9, 0.6 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H), 1.10-1.22 (m, 2H), 1.26-1.36 (m, 4H), 1.49-1.60 (m, 4H), 2.02-2.09 (m, 1H), 2.37-2.45 (m, 2H), 3.43 (t, J = 9 Hz, 1H), 4.09 (t, J = 7.8 Hz, 1H), 4.24 (dd, J = 16.2, 15 Hz, 2H), 6.76-6.84 (m, 2H), 6.86 (t, J = 1.2 Hz, 1H), 6.92 (t, J = 1.2 Hz, 1H), 7.32 -7.41 (m, 2 H); IR (CHCl 3 ) ν 3373, 3301, 2931, 2867, 1615, 1599, 1498, 1269, 1107, 1076, 965 cm −1 .
<실시예 8><Example 8>
(-)-(2R-트랜스)-2-(2,4-디플루오로페닐)-2-[1H-(이미다졸-1-일)메틸]-4-(4-아미노-5-메틸헥실)테트라하이드로푸란의 제조(-)-(2R-trans) -2- (2,4-difluorophenyl) -2- [1H- (imidazol-1-yl) methyl] -4- (4-amino-5-methylhexyl Preparation of Tetrahydrofuran
본 실시예에서 제조하고자 하는 화합물은 상기 화학식 17로 표시되는 화합물로서 반응식 2에서12b화합물 중 Z1및 Z2가 모두 F인 화합물(이하12b'로 표시)이다.The compound to be prepared in the present Example is a compound represented by Chemical Formula 17, wherein Z 1 and Z 2 in the 12b compound of Scheme 2 are both F (hereinafter referred to as 12b ′ ).
상기 실시예 3과 동일한 방법으로 실시예 6에서 제조한 화합물11b'45mg, 하이드록실아민염산염 14mg, 피리단 33㎕ 및 무수 에탄올 2.5ml을 사용하여 중간 생성물 36mg을 얻었다. 이 중간 생성물 36mg, 메탄올 2.5ml 및 니켈(II)클로라이드육수화물 44mg 및 소디움보로하이드라이드 35mg을 사용하여 목적물인 상기 화학식 17의 화합물12b'17mg을 제조하였다.In the same manner as in Example 3, 36 mg of the intermediate product was obtained using 45 mg of the compound 11b ′ prepared in Example 6, 14 mg of hydroxylamine hydrochloride, 33 μl of pyridan, and 2.5 ml of anhydrous ethanol. 36 mg of this intermediate product, 2.5 ml of methanol and 44 mg of nickel (II) chloride hexahydrate and 35 mg of sodium borohydride were used to prepare 17 mg of the compound of the formula ( 12b ' ).
화합물12b'의 화학적 특징 요약:Summary of Chemical Properties of Compound 12b ' :
1H-NMR(CDCl3)δ0.83(d, J=6.9Hz, 3H), 0.87(dd, J=6.9, 0.5Hz, 3H), 1.11-1.24(m, 4H), 1.24-1.36(m, 2H), 1.40-1.58(m, 3H), 1.68-1.79(m, 2H), 2.39-2.45(m, 1H), 2.49-2.58(m, 1H), 3.34(t, J=9Hz, 1H), 4.04-4.19(m, 3H), 6.79-6.87(m, 3H) 6.95(s, 1H), 7.40-7.50(m, 2H); IR(CHCl3)ν 3375, 3301, 2933, 2868, 1616, 1598, 1498, 1269, 1106, 965cm-1. 1 H-NMR (CDCl 3 ) δ 0.83 (d, J = 6.9 Hz, 3H), 0.87 (dd, J = 6.9, 0.5 Hz, 3H), 1.11-1.24 (m, 4H), 1.24-1.36 (m , 2H), 1.40-1.58 (m, 3H), 1.68-1.79 (m, 2H), 2.39-2.45 (m, 1H), 2.49-2.58 (m, 1H), 3.34 (t, J = 9 Hz, 1H) 4.04-4.19 (m, 3H), 6.79-6.87 (m, 3H) 6.95 (s, 1H), 7.40-7.50 (m, 2H); IR (CHCl 3 ) ν 3375, 3301, 2933, 2868, 1616, 1598, 1498, 1269, 1106, 965 cm −1 .
<시험예><Test Example>
테트라하이드로푸란 화합물들의 시험관 내 항진균 활성 측정In Vitro Antifungal Activity Determination of Tetrahydrofuran Compounds
상기 실시예에서 제조한 화합물7a',7b',9a',9b',11a',11b',12a'및12b'에 대해에 대해 시험관내 항진균 활성을 비교 시험하였다.In vitro antifungal activity was tested for compounds 7a ' , 7b' , 9a ' , 9b' , 11a ' , 11b' , 12a ' and 12b' prepared in the above examples.
멸균 건조된 이스트 추출물 맥아추출물 아가(yeast extract malt extract agar) 플레이트에 MOPS 완충액을 0.165M이 되도록 가한 다음 pH를 7.0으로 조절한 RPMI-1640 브로스(Sigma Co., w/L-glutamin, wo/NaHCO3)를 가한 다음, 상술한 시험용 화합물들을 0.05-100㎍/ml의 농도 범위로 희석하여 플레이트에 가하였다. 다음으로, 하기 표 1에 나타낸 시험균주의 농도가 1 x 104CFU/ml가 되도록한 시험균액을 상기 배지에 접종하고 30℃에서 48시간(이스트) 또는 72시간(몰드) 배양하였다.RPMI-1640 broth (Sigma Co., w / L-glutamin, wo / NaHCO) was added to a sterile dried yeast extract malt extract agar plate with MOPS buffer at 0.165M and pH adjusted to 7.0. 3 ) was added, and the test compounds described above were diluted to a concentration range of 0.05-100 µg / ml and added to the plate. Next, the test bacteria solution in which the concentration of the test strain shown in Table 1 was 1 × 10 4 CFU / ml was inoculated into the medium and incubated at 30 ° C. for 48 hours (yeast) or 72 hours (mould).
동일한 조건 하에 시험용 화합물을 부가하지 않고 배양한 대조표본과 비교하여 최소 억제 농도(MIC)를 측정하였다. 시험균의 성장이 90% 이상 억제되는 농도를 MIC로 하였으며 그 결과를 표 1에 나타냈다.The minimum inhibitory concentration (MIC) was determined by comparison with a control culture incubated without adding the test compound under the same conditions. The concentration at which the growth of the test bacteria was inhibited by 90% or more was set to MIC, and the results are shown in Table 1.
<비교 시험예 1>Comparative Test Example 1
상술한 항진균 시험과 동일한 방법으로 종래의 아졸계 항진균제인 플루코나졸에 대해 시험관내 항진균 활성을 시험하여 그 결과를 표 1에 나타냈다.In vitro antifungal activity was tested against fluconazole, a conventional azole antifungal agent, in the same manner as the antifungal test described above, and the results are shown in Table 1.
<비교 시험예 2>Comparative Test Example 2
상술한 항진균 시험과 동일한 방법으로 종래의 아졸계 항진균제인 이트라코나졸에 대해 시험관내 항진균 활성을 시험하여 그 결과를 표 1에 나타냈다In vitro antifungal activity was tested against the conventional azole antifungal agent itraconazole in the same manner as the antifungal test described above, and the results are shown in Table 1.
상기 표 1에서 A는 ATCC를 나타내고, K는 KFCC를 나타낸다.In Table 1, A represents ATCC and K represents KFCC.
표 1의 결과를 보면, 화합물7a',7b',11a'및11b'의 케톤 화합물이 화합물9a',9b',12a'및12b'의 아민 화합물보다 뛰어난 항진균 활성을 보였으며, (2R)-시스 구조를 가진 화합물 이 (2R)-트랜스의 구조를 가진 화합물보다 항진균 활성을 보였다.The results in Table 1 show that the ketone compounds of compounds 7a ' , 7b' , 11a ' and 11b' showed better antifungal activity than the amine compounds of compounds 9a ' , 9b' , 12a ' and 12b' , and (2R)- Compounds with cis structure showed more antifungal activity than compounds with (2R) -trans structure.
또한, 화합물11a'와11b'는 종래의 플루코나졸보다는 월등하고, 이트라코나졸과는 비교될 만한 항진균 활성을 보였으며, 특히 칸디다(Candida)균에 대한 항진균에 대한 활성은 이트라코나졸보다 우수함을 보였다.In addition, the compound 11a 'and 11b' are activated for antifungal about showed the antifungal activity of interest to be compared and superior than conventional fluconazole and itraconazole, in particular Candida (Candida) strain showed a superior itraconazole.
상술한 바와 같이 본 발명에 따른 테트라하이드로푸란 유도체는 시험관 내에서 우수한 항진균 활성을 보였으며, 이를 항진균적으로 유효량 포함하는 약학적 조성물은 항진균제로서 사용할 수 있다.As described above, the tetrahydrofuran derivative according to the present invention showed excellent antifungal activity in vitro, and a pharmaceutical composition containing an antifungal effective amount thereof can be used as an antifungal agent.
본 발명은 실시예를 참고로 설명되었으나 이는 예시적인 것에 불과하며, 본 발명이 속하는 기술분야에 통상의 지식을 가진 자라면 이로부터 다양한 변형 및 균등한 실시가 가능하다는 점을 이해할 것이다. 따라서, 본 발명의 진정한 기술적 보호 범위는 첨부된 특허청구범위의 기술적 사상에 의해 정해져야 할 것이다.Although the present invention has been described with reference to the embodiments, these are merely exemplary, and those skilled in the art will understand that various modifications and equivalent implementations are possible therefrom. Therefore, the true technical protection scope of the present invention will be defined by the technical spirit of the appended claims.
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|---|---|---|---|---|
| JPS649988A (en) * | 1987-05-29 | 1989-01-13 | Scras | Novel 5-(omega-ammonioacyloxymethylene) tetrahydrofurans and tetrahydrothiophenes, manufacture and medicinal composition |
| US5210198A (en) * | 1984-01-26 | 1993-05-11 | Rhone-Poulenc Agrochimie | Fungicides containing triazole and oligoether groups |
| US5403937A (en) * | 1993-04-30 | 1995-04-04 | Schering Corporation | Process for preparing intermediates for the synthesis of antifungal agents |
| JPH10231296A (en) * | 1997-02-19 | 1998-09-02 | Schering Plough Corp | Tetrahydrofuran-based antifungal agent |
-
1999
- 1999-12-14 KR KR1019990057618A patent/KR100326276B1/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5210198A (en) * | 1984-01-26 | 1993-05-11 | Rhone-Poulenc Agrochimie | Fungicides containing triazole and oligoether groups |
| JPS649988A (en) * | 1987-05-29 | 1989-01-13 | Scras | Novel 5-(omega-ammonioacyloxymethylene) tetrahydrofurans and tetrahydrothiophenes, manufacture and medicinal composition |
| US5403937A (en) * | 1993-04-30 | 1995-04-04 | Schering Corporation | Process for preparing intermediates for the synthesis of antifungal agents |
| JPH10231296A (en) * | 1997-02-19 | 1998-09-02 | Schering Plough Corp | Tetrahydrofuran-based antifungal agent |
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| Publication number | Publication date |
|---|---|
| KR20010056234A (en) | 2001-07-04 |
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